Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

    Preclinical and Clinical Evidence for the Role of Resveratrol in the Treatment of Cardiovascular Diseases Beshay N.M. Zordoky, Ian M. Robertson, Jason R.B. Dyck PII: DOI: Reference:

S0925-4439(14)00322-6 doi: 10.1016/j.bbadis.2014.10.016 BBADIS 64095

To appear in:

BBA - Molecular Basis of Disease

Received date: Revised date: Accepted date:

2 September 2014 24 October 2014 27 October 2014

Please cite this article as: Beshay N.M. Zordoky, Ian M. Robertson, Jason R.B. Dyck, Preclinical and Clinical Evidence for the Role of Resveratrol in the Treatment of Cardiovascular Diseases, BBA - Molecular Basis of Disease (2014), doi: 10.1016/j.bbadis.2014.10.016

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Preclinical and Clinical Evidence for the Role of Resveratrol in the Treatment of Cardiovascular Diseases

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Zordoky et al. Resveratrol and Cardiovascular Diseases

Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

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Beshay N. M. Zordoky*1, Ian M. Robertson*1 and Jason R.B. Dyck 1,2

* Equally contributed co-authors 2

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Contact Information: Dr. Jason R. B. Dyck, 458 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2; Telephone: (780) 492-0314; Fax: (780) 4929753; Email: [email protected]

Abstract: 225 words Document: 13618 words Figures: 3 Tables: 7

ACCEPTED MANUSCRIPT Abstract

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Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of CVD, the incidence of CVD is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with CVD. Although the majority of the existing pharmacotherapies for CVD are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous antioxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulinsensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous CVDs, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of CVD and provide information about the physiological and molecular signaling mechanisms involved.

Keywords: Resveratrol – Cardiovascular diseases

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ACCEPTED MANUSCRIPT Introduction

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Cardiovascular diseases (CVDs) are a class of diseases that affect the heart and/or the blood vessels [1]. The most common examples of CVDs include hypertension and coronary artery disease (CAD). Of the 83.6 million American adults with CVD, ~93% are hypertensive and ~18% have atherosclerosis [2]. If left untreated or with poor clinical management, hypertension and/or atherosclerosis can develop into arrhythmias, ischemic heart disease, myocardial infarction, and eventually, heart failure [2]. The World Health Organization (WHO) ranks CVDs as the leading cause of death worldwide – with an estimated 17.3 million people dying of CVD annually [1]. The incidence of CVD is expected to continue to rise and along with the increase in disease prevalence, the expected worldwide CVD-related deaths are projected to climb to 23.3 million by 2030. Based on these statistics, it is apparent that new therapies are needed to combat the enormous burden of CVDs on the quality and length of life of the global population.

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Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a non-flavonoid polyphenolic compound belonging to the stilbenes group [3]. It is found in many plant based foods and beverages including red wine, grapes, a variety of berries, and peanuts [4]. Resveratrol is considered a phytoalexin, because it is produced by the plant under stress conditions [5]. Although resveratrol exists in either the cis or trans form, it is the trans isomer that is a more effective anti-oxidant [6], is more bioactive [7], and more stable [7, 8]. The presence of resveratrol, along with other polyphenolic compounds in red wine has garnered much attention, especially with regards to their potential role in the protection against CVD [9]. Indeed, red wine is thought to be responsible for the “French Paradox”, a term used to describe the low incidence of CVD in the French population despite their high intake of saturated fats [10]. However, resveratrol is present at very low concentration in red wine [11], suggesting that the French Paradox is mediated through several dietary and life-style factors not through resveratrol alone. In fact, although resveratrol is present in foods and beverages, the concentrations are quite low and research into resveratrol has largely involved resveratrol supplements [12, 13]. Regardless of whether or not the French Paradox involves resveratrol, the antiplatelet activity of resveratrol was identified as one of its first cardioprotective roles [14], and in the following 20 years, a plethora of preclinical studies have demonstrated the beneficial effects of resveratrol in the prevention and/or treatment of several CVDs in various animal models [4]. Similarly, mechanistic studies have identified a multitude of molecular targets for resveratrol [15]. Nevertheless, the confirmation of these promising effects in human clinical trials is still very limited with several inconsistent findings and a few unfavorable results [16]. The objective of this review is to discuss the current knowledge about the potential beneficial effects of resveratrol in several CVDs, including hypertension, atherosclerosis, ischemic heart diseases, heart failure, arrhythmia, and stroke. The review will discuss important molecular targets of resveratrol implicated in its cardiovascular protective effects. Thereafter, the results of preclinical studies will be compared to those of recent clinical studies that show the cardiovascular effects of resveratrol in human subjects. The challenges that face translating the preclinical findings to clinical settings will also be discussed.

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Hypertension has been shown to be a major risk factor for CVDs [17]. The prevalence of hypertension is estimated to be more than 25% of the adult population in developed countries [18] and in the United States, approximately 33% of the adult population over the age of 20 have hypertension [2]. Although there are several classes of drugs used to treat hypertension, the target blood pressure (BP) values may not be achieved in some patients even after combining 3 or more anti-hypertensive medications [19]. In addition, not all anti-hypertensive medications can protect against the end-organ damage commonly observed in hypertensive patients (e.g. cardiac hypertrophy, hypertensive nephropathy, cerebrovascular complications, and hypertensive retinopathy [20]). Therefore, there is still a clinical need for an antihypertensive medication that can safely lower BP as well as offer end-organ protection. Of importance, several investigators have demonstrated that resveratrol can lower BP in experimental animal models of hypertension (Table 1). In addition, resveratrol can offer endorgan protection due to its cardioprotective [21], nephroprotective [22], neuroprotective [23], and retinoprotective properties [24]. Based on these studies, resveratrol may be a promising antihypertensive medication warranting further investigation.

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The anti-hypertensive effect of resveratrol (10 – 320 mg/kg body weight/day) has been demonstrated in several animal models of hypertension including the spontaneously hypertensive rat (SHR) model [25, 26], the angiotensin (Ang) II infused mouse model [25, 27], the two-kidney one-clip hypertensive rat [28], and in partially nephrectomized rats [29]. In general, lower doses of resveratrol (2.5 mg/kg/day) did not affect BP in several other studies performed in the same animal models [30-32]. Interestingly, while these findings suggest that the anti-hypertensive effects of resveratrol are dose-dependent, resveratrol (1 mg/kg/day) has been shown to reduce BP in DOCA-salt hypertensive rats [33], suggesting that under certain conditions, even low doses of resveratrol can lower BP and that the BP lowering effect of resveratrol is model-dependent. Indeed, relatively low doses of resveratrol (5 – 10 mg/kg/day) were sufficient to lower BP in hypertension animal models associated with insulin resistance [34-37], suggesting that resveratrol may be more effective in lowering BP in patients with diabetes or metabolic syndrome. In agreement with this, resveratrol treatment (10 mg/kg/day) reduced systolic BP in obese Zucker rats, yet had no effect on the BP of lean rats [34]. Similarly, resveratrol treatment (20 mg/kg/day) significantly lowered systolic and diastolic BP in female rats fed high fat diet, but not in rats fed normal chow diet [38]. In an effort to understand the potential of resveratrol to augment the effect of other antihypertensive medications, Thandapilly et al. administered low dose resveratrol with and without hydralazine to SHR [31]. Although a low dose of resveratrol (2.5 mg/kg/day) alone did not affect the systolic or the diastolic pressure in the SHR [31, 39], the combination of hydralazine and resveratrol treatment was significantly more effective than hydralazine alone in reducing both systolic and diastolic BP [31]. Although these findings are important, hydralazine is rarely used in the clinic to treat hypertension. As a result, to translate these findings to humans, it will be

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essential to confirm these interesting findings with more commonly prescribed anti-hypertensive medications such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, Ca2+ channel blockers, beta blockers, and thiazide diuretics as well as understand the mechanism involved.

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Interestingly, some studies that did not report a BP lowering effect of resveratrol have still demonstrated other protective effects on the vasculature. For instance, low dose resveratrol treatment (0.448 mg/L to 4.48 mg/L in drinking water) did not reduce systolic BP in SHR, but it improved endothelium-dependent relaxation to acetylcholine (Ach) in thoracic aortic rings from hypertensive SHRs [40]. Similarly, resveratrol treatment (50 mg/L in drinking water for 3 weeks) has also been shown to increase Ach-induced relaxation and decrease phenylephrine- and Ang II-induced contraction in endothelium-intact aortic rings of healthy male and female rats [41]. Nevertheless, resveratrol had no effect on endothelium-dependent relaxation in thoracic aortic rings from normotensive Sprague Dawley rats [40], suggesting a more pronounced effect on damaged vessels compared to healthy ones.

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Since age, obesity, and diabetes are important risk factors for endothelial dysfunction [42], resveratrol treatment (2400 mg/kg of food) has been shown to prevent both age-related and obesity-related decline in endothelial function [43]. Similarly, the maximal relaxation to Ach was improved by about 75% in diabetic rabbits treated with resveratrol (50 mg/L of drinking water) [44]. Moreover, resveratrol suppressed basal superoxide production and lipid peroxide levels in the aortas of the diabetic rats protecting the endothelial integrity from diabetes. Of importance, these protective effects occurred in the absence of changes in blood glucose or lipids [44]. Overall, the protective effect of resveratrol on the vasculature may play an important role in the prevention of hypertension and/or in the protection against hypertension-induced end organ damage in the long-term. The anti-hypertensive effect of resveratrol is thought to be mediated through both endothelium-dependent and endothelium-independent mechanisms (Fig. 1) [45]. With regard to its endothelium-dependent effects, resveratrol supplementation has been shown to improve flow-mediated vasodilation, a surrogate for endothelial function, in several animal models [28, 40, 41, 43]. Similarly, resveratrol has been shown to stimulate endothelium-dependent relaxation of isolated carotid arteries [46] and aortic rings [47]. These endothelium-dependent vasodilatory effects of resveratrol appear to be mediated via improved bioavailability of nitric oxide (NO) through increasing endothelial nitric oxide synthase (eNOS) expression and activity [48, 49]. NO is generated by three isoforms of NO synthase (NOS), eNOS, neuronal NOS (nNOS), and inducible NOS (iNOS) [50]. eNOS is of particular importance in cardiovascular physiology as it regulates vascular tone via the release of NO in the vascular endothelium [50]. The mechanisms for increased NO bioavailability during resveratrol treatment have been proposed to involve the effects of resveratrol on silent information regulator 1 (SIRT1), AMPactivated protein kinase (AMPK), and reactive oxygen species (ROS). SIRT1 is a class III histone deacetylase responsible for various biological effects including the stimulation of NO production by deacetylating eNOS at lysine residues [51]. In

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addition, a resveratrol-induced increase in eNOS expression has been attenuated by knockingdown endogenous SIRT1 levels by RNAi [52], and thus it appears that SIRT1 activation by resveratrol mediates both activity and expression of eNOS. AMPK, a major regulator of energy metabolism [53], also regulates NO bioavailability via eNOS. AMPK can directly phosphorylate and activate eNOS on serine 1177, resulting in a subsequent increase in NO production [54]. It has been shown that resveratrol activates AMPK to stimulate NO production [25]. The dependence of AMPK in this process has been demonstrated with pharmacological inhibition of AMPK that also abolished the ability of resveratrol to improve endothelium-dependent vasodilation in aortic rings [47], and resveratrol-induced eNOS activation in human umbilical vein endothelial cells (HUVECs) [25]. Of interest, a recent study has shown that administration of the AMPK inhibitor, compound C, significantly reduced the beneficial effect of resveratrol on lowering BP in Ang II-infused mice [27], thus confirming the important role of AMPK in mediating the vasodilatory effect of resveratrol.

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In addition to the involvement of SIRT1 and AMPK in mediating the endotheliumdependent vasodilatory effects of resveratrol, resveratrol has been shown to enhance NOS activity by increasing tetrahydrobiopterin (BH4) levels, a cofactor necessary for proper function of NOS [55]. The endothelium-dependent vasodilatory effect of resveratrol has also been attributed to the anti-oxidant properties of resveratrol [41, 56]. Resveratrol has both intrinsic antioxidant properties, as well as anti-oxidant effects secondary to up-regulation of endogenous anti-oxidant enzymes [57]. Of importance, resveratrol has been shown to attenuate vascular oxidative stress by up-regulation of superoxide dismutase (SOD) through a nuclear factor erythroid-2 related factor-2 (NRF2)-dependent mechanism [55]. Interestingly, there is multiple cross-talk between anti-oxidant enzymes and the SIRT1 and AMPK-dependent pathways. Indeed, resveratrol can reduce oxidative stress in endothelial cells via increased endothelial SIRT1 expression [58]. In addition, SIRT1 has been shown to mediate the activating effect of moderate dose of resveratrol on AMPK [59]. As such, it appears as though all of these pathways can signal one another to mediate the effects of resveratrol during different conditions. In addition to stimulating endothelium-dependent vasodilation, resveratrol has also been shown to have endothelium-independent vasodilatory mechanisms. In human internal mammary artery rings with denuded endothelium, resveratrol has been shown to cause a concentrationdependent relaxation through a K+ channel-mediated mechanism [60]. Cao et al. demonstrated that the BP lowering effect of resveratrol may be attributed to the AMPK-mediated inhibition of vascular smooth muscle cell (VSMC) contractility through the suppression of myosin phosphatase-targeting subunit 1 (MYPT1)/myosin light chain (MLC) phosphorylation [27]. Furthermore, resveratrol reduces the expression of vasoconstrictor molecules such as Ang II and endothelin (ET)-1 [29, 61]. Resveratrol inhibits strain-induced ET-1 gene expression by interfering with the ERK1/2 pathway through attenuation of ROS formation [62]. Since the vascular tone depends on cytoplasmic Ca2+ concentration [Ca2+]i in VSMC, effects of resveratrol on Ca2+ handling can contribute to its vasodilatory effects [63]. Indeed, resveratrol has been shown to reduce both vasopressin- and Ang II-induced increase in [Ca2+]i in A7r5 aortic smooth muscle cells [64]. Similarly, resveratrol has been shown to attenuate both extracellular Ca2+

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influx by inhibiting L-type Ca2+ channels, and intracellular Ca2+ release by inhibiting inositol triphosphate (IP3)-gated Ca2+ channels, leading to vasorelaxation of rat abdominal aortic rings [65]. In addition to the direct effects on vascular cells, a central effect of resveratrol has also been demonstrated. For instance, resveratrol microinjection into the rostral ventrolateral medulla lowered BP and heart rate by decreasing the sympathetic vasomotor tone [66], which may be mediated through NO synthesis and a decrease in Ca2+ influx [66]. Resveratrol has also been shown to activate AMPK in the nucleus tractus solitarii (NTS) in the brainstem of fructose-fed rats [67], and it has been proposed that this activation lowers BP through decreasing ROS generation, enhancing Akt-nNOS pathway activity, and up-regulating SOD2 levels in the NTS [67].

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In addition to systemic hypertension, resveratrol has also been shown in some animal studies to protect against and/or reverse pulmonary hypertension [68]. In models of monocrotaline-induced pulmonary hypertension, resveratrol has been shown to prevent the increase in right-ventricular systolic pressure and right ventricular hypertrophy [69, 70]. In this model, resveratrol improved endothelial function, attenuated inflammation and oxidative stress, and inhibited proliferation of pulmonary artery smooth muscle cells [70]. In addition, resveratrol has also been shown to reverse established pulmonary hypertension when it was administered 28 days after the monocrotaline injection [71, 72]. In a model of pulmonary thromboembolisminduced pulmonary hypertension, two doses of resveratrol (10 mg/kg; IP) significantly reduced mean pulmonary artery pressure through down-regulation of monocyte chemo-attractant protein-1 (MCP-1), and P-p38 mitogen-activated protein kinase (MAPK) [73]. Together, these studies show that resveratrol has multiple beneficial effects on the vasculature and may hold promise for the treatment and/or prevention of systemic hypertension as well as pulmonary hypertension. Clinical studies:

Compared to the amount of preclinical data about the effects of resveratrol on BP regulation, there is much less information available from studies that investigate the effects of resveratrol on BP in humans. A recent meta-analysis of 6 randomized controlled trials investigated the effect of resveratrol on BP and reported that high doses of resveratrol (≥ 150 mg/day) significantly reduced systolic BP [74-76], while lower doses had no effect on BP [7779]. Although both high doses and low doses had no effect on diastolic BP, it has been suggested that systolic BP is a more important CVD risk factor than diastolic BP [80]. However, it is important to mention that this meta-analysis included a study that used resveratrol-rich extract instead of pure resveratrol [77], thus potentially confounding the conclusions. Since the reduction in systolic BP in two of these studies occurred in association with better glycemic control in the resveratrol groups [74, 75], and the BP lowering effect of resveratrol was accompanied by general improvement of several metabolic parameters in another study [76], it is not known whether the anti-hypertensive effect of resveratrol is due to a direct vasodilatory effect, or secondary to the correction of these metabolic perturbations. Nevertheless, the effects observed in humans re-capitulate most of the animal studies that showed the same dosedependent effect of resveratrol on systolic BP (Table 1). Since the aforementioned studies

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Atherosclerosis

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investigated the BP lowering effect of resveratrol in healthy subjects or in normotensive patients with metabolic conditions, it was not surprising that resveratrol did not exert a substantial BP lowering effect. In agreement with this, in healthy non-obese individuals, resveratrol along with 9 other dietary supplements did not affect arterial stiffness, endothelial function, biomarkers of inflammation and oxidative stress, and cardiometabolic risk factors [81]. However, the systolic and diastolic BPs of the participants of this study were already optimum, average of 109 and 66 mmHg, respectively [81]. Therefore, it is likely that the BP lowering effect of resveratrol would be more pronounced if resveratrol is administered to hypertensive individuals. Consistent with this notion, resveratrol has been shown to enhance Ach-evoked vasorelaxation in blood vessels from patients with hypertension and dyslipidemia, but not in vessels from non-hypertensive nondyslipidemic subjects [55]. Although resveratrol supplementation in healthy obese adults and in patients with metabolic syndrome did not affect systolic or diastolic BP values some studies, it caused a significant improvement of flow-mediated dilatation in these subjects [79, 82], suggesting that resveratrol may prevent the development of hypertension in these subjects. However, this is only speculation as the duration of these clinical trials was too short to determine the long-term consequence of the intervention. Unfortunately, there is no clinical trial that we are aware of that investigated the BP lowering effect of resveratrol in hypertensive patients, which should be the target population for this effect (Table 7).

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Atherosclerosis can contribute to multiple CVDs through luminal narrowing and/or thrombus formation that obstruct blood flow to the heart (CAD), brain (ischemic stroke), or lower extremities (peripheral vascular diseases) [83]. The generation of atherosclerotic plaques is usually initiated by the concentration-dependent transport of low density lipoproteins (LDL) into the arterial wall, followed by modification of these lipids by oxidation and/or inflammation, invasion of macrophages and their transformation to foam cells, infiltration of smooth muscle cells, and production of fibrin and extracellular matrix [84]. Interestingly, all of these detrimental processes can be attenuated by resveratrol [85]. For example, dyslipidemia is known to initiate the atherosclerotic process with LDL identified as a the deleterious lipoprotein and the high density lipoprotein (HDL) identified as the beneficial one [86]. Preclinical studies: Several animal studies have shown that resveratrol can lower plasma levels of total and LDL cholesterol, as well as triglycerides, and increase the level of HDL cholesterol (Table 2) [87-91]. Of clinical significance, resveratrol potentiated the protective effect of pravastatin, a commonly prescribed anti-hypercholesterolemic medication, when administered together to male Sprague Dawley rats fed a high cholesterol diet [90]. The main proposed mechanism of resveratrol cholesterol-lowering effect is the down-regulation of the hepatic 3-hydroxy 3methylglutaryl Coenzyme A (HMG-CoA) reductase enzyme, a key enzyme in cholesterol biosynthesis [88-90]. Another proposed mechanism for the cholesterol-lowering effect of

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resveratrol is via increased liver expression of cholesterol 7α-hydroxylase (CYP7A1) which leads to increased bile acid synthesis and secretion, thus lowering the plasma level of total and LDL cholesterol [92]. Moreover, resveratrol has also been shown to increase the expression of LDL receptors in hepatocytes in vitro, thus increasing the hepatic uptake of LDL, through an AMPK independent mechanism [93]. Although these studies suggest that the lipid lowering of effects of resveratrol likely contribute to preventing atherosclerosis, some other studies have demonstrated an anti-atherosclerotic effect of resveratrol without lowering the lipid plasma levels [94-96], suggesting that resveratrol may also interfere with other steps in the pathogenesis of atherosclerosis.

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The second step in the process of atherosclerosis is LDL oxidation, which promotes macrophage migration into the vessel wall. Following this, macrophages take up oxidized LDL and are transform into foam cells that initiate the atherosclerotic lesion [97]. Resveratrol has been shown to reduce oxidized LDL cholesterol, an effect that was attributed to the anti-oxidant effect of resveratrol [96, 98]. Indeed, resveratrol has both intrinsic anti-oxidant properties in addition to its ability to induce several endogenous anti-oxidant enzymes such as SOD and NADPH quinine-oxidoreductase [99, 100]. Resveratrol has also been shown to impede the cholesterol accumulation in human macrophages by mechanisms that involve increased expression of reverse cholesterol transport proteins such as peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α (LXRα), 27-hydroxylase, and ATP-binding cassette transporter A1 (ABCA1) [98, 101]. Since inflammation is essential for the progression of atherosclerosis, the anti-atherosclerotic effects of resveratrol can also be explained by its antiinflammatory properties [102]. Consistent with this, resveratrol treatment has been shown to inhibit interleukin (IL)-6 and IL-8 production in human coronary artery smooth muscle cells [103], inhibit IL-6 release by stimulated macrophages [104], and reduce the serum levels of IL-1β, IL-6, and tumor necrosis factor-α (TNFα) in an atherosclerotic rabbit model [105]. Resveratrol has also been shown to inhibit TNFα-mediated adhesion of neutrophils and monocytes to endothelial cells by reducing the expression of the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) through nuclear factor-kappaB (NF-κB) inhibition [106, 107]. Similarly, resveratrol has been shown to reduce hyperglycemia-induced ICAM-1 expression in endothelial cells via the p38 MAPK pathway [108]. In cultured endothelial cells, the anti-inflammatory effects of resveratrol have been attributed to inhibition of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) [109, 110]. In agreement with the known cross talk between inflammation and oxidative stress, resveratrol pre-treatment strongly suppressed LPS-induced foam cell formation through the inhibition of LPS-induced NADPH oxidase-1 and ROS generation [111]. Similarly, resveratrol has been shown to protect endothelial cells by inhibiting NADPH-oxidase and attenuating ROS production [112, 113]. Resveratrol also counteracts 7-oxo-cholesterol-induced inflammation and NF-κB activation in human macrophages, suggesting an important role of resveratrol to protect against the pro-atherogenic effect of oxysterols [114]. Furthermore, resveratrol has been shown to prevent the age-associated pro-inflammatory phenotype in vascular smooth muscle cells of a non-human primate, suggesting a vasoprotective effect of resveratrol in animal models of aging [115]. The vascular protective effect of resveratrol can also be attributed to the increase of

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serum adiponectin level [116], which is known to protect the vasculature through a number of mechanisms [117]. Therefore, the anti-oxidant and the anti-inflammatory properties of resveratrol may also mediate its anti-atherogenic effect through inhibiting LDL oxidation, macrophage migration, and macrophage transformation into foam cells.

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Later in the course of atherosclerosis, VSMCs migrate to the atherosclerotic plaque where they proliferate and secrete extracellular matrix to form a capped fibrous lesion [85]. Importantly, resveratrol has been shown to suppress both VSMCs migration [118-120], and proliferation [121-124]. In addition, resveratrol has been shown to inhibit neointimal cell proliferation after vascular injury in an eNOS-dependent mechanism [125]. VSMC mineralization is another common feature of atherosclerosis which can also be reduced by resveratrol through opposing apoptosis and oxidative stress [83]. However, the effect of resveratrol on VSMC differentiation is controversial. While resveratrol has been demonstrated to induce VSMC differentiation through SIRT1 and AMPK-dependent pathways [126], resveratrol has also been shown to induce VSMC dedifferentiation by regulating myocardin and serum response factor (SRF)-mediated VSMC gene expression [127]. Therefore, resveratrol can protect against atherosclerosis through its anti-proliferative, anti-migratory, and anti-mineralizing effects on the VSMCs. However, further research is needed to elucidate the effect of resveratrol on VSMC differentiation and how this may contribute to its anti-atherogenic effect.

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In humans, after decades of slow progression, the atherosclerotic plaques may suddenly rupture causing life-threatening coronary thrombosis [83]. Interestingly, several studies have shown that resveratrol can also inhibit important steps in the process of thrombogenesis [85]. Olas et al. have shown that resveratrol decreases platelet adhesion to both collagen and fibrinogen after activation with LPS or thrombin [128]. There are several proposed mechanisms to explain the anti-platelet effect of resveratrol. For instance, resveratrol has been shown to inhibit collagen-induced platelet activation via inhibition of the p38 MAPK and activation of the NO/cGMP pathways [129]. In hypercholesterolemic rats, resveratrol (20 mg/kg/day) for 20 days inhibited the expression of several markers of platelet activation [91]. It has also been shown that resveratrol inhibits platelet activation through the inhibition of protein kinase C (PKC) [130], and phospholipase C beta [131]. In addition, resveratrol has been shown to simultaneously inhibit platelet aggregation and induce platelet apoptosis [132]. Conversely, although a mixture of grape polyphenolic compounds inhibited platelet activation, resveratrol alone was unable to inhibit platelet activation in one study [133]. However, resveratrol inhibits epinephrine- and collagen-induced aggregation of platelets from aspirin-resistant patients [134], suggesting that resveratrol may be a second-line anti-platelet in these aspirin-resistant patients. This is particularly important from a clinical perspective since aspirin remains the most clinically used anti-platelet medication and up to 20% of serious vascular events in high risk vascular patients can be attributed to aspirin-resistance [135]. Clinical studies: In contrast to the promising results from animal studies, clinical trials that investigated the effect of resveratrol on plasma lipid profile in human subjects have not been as clear (Table

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7). For instance, in patients with type 2 diabetes, daily resveratrol dose of 250 – 1000 mg caused a significant reduction in LDL-cholesterol in two different studies [74, 75]. Similarly, there was a significant reduction in plasma triglyceride levels in healthy obese men and healthy adult smokers treated with resveratrol 150 mg/day and 500 mg/day, respectively [76, 136]. In another study in patients treated with statins and at high risk of CVDs, daily ingestion of 350 mg resveratrol-enriched grape extract containing 8 mg resveratrol for 6 months caused a 20% reduction of oxidized LDL cholesterol but only a modest 4.5% reduction in LDL cholesterol [137], suggesting that the anti-oxidant effect of resveratrol may be more important than its LDL cholesterol-lowering effect. Since a mixture of polyphenolic compounds was used in this study, this effect may be attributed to the synergistic effect between resveratrol and the other polyphenolic compounds, rather than due to resveratrol alone.

Stroke

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In contrast to these aforementioned studies, resveratrol had no effect on lipid profile in several other studies [78, 79, 82, 138, 139]. In addition, a meta-analysis of 7 clinical trials concluded that resveratrol lacks a significant effect on plasma lipid concentrations [140]. Nevertheless, there were several limitations mentioned in this meta-analysis including the small size and heterogenecity of the study populations, heterogeneous study designs, resveratrol dose, and duration of resveratrol supplementation [140]. In addition to these limitations, the meta-analysis included two studies that used resveratrol-rich extracts instead of pure resveratrol [137, 141], again, potentially confounding the conclusions. Therefore, the anti-atherosclerotic effect of resveratrol still needs to be confirmed by large long-term, well-controlled clinical trials that assess the effect of resveratrol on all the aforementioned steps in the atherosclerotic process, not only the plasma lipid profile.

The anti-atherosclerotic effects of resveratrol along with improving endothelial function have also been attributed to the protective effect of resveratrol against ischemic stroke [142]. As early as 2001, resveratrol has been shown to reduce the infarct size in a rat model of focal cerebral ischemia [143]. Although the mechanism of this protective effect was not thoroughly investigated, the authors attributed it to the anti-platelet, vasodilatory, and anti-oxidant effects of resveratrol [143]. In another animal model of recurrent ischemic stroke, resveratrol has been shown to reduce the extent of brain damage, preserve blood brain barrier function, reduce inflammation, and protect the endothelial cells [142]. In this instance, the authors suggest that the endothelial protective effect of resveratrol is, at least in part, SIRT1 dependent, but not NOdependent [142]. Another in vitro study has shown that resveratrol promotes angiogenesis in cerebral endothelial cells by activation of PI3K/Akt and MAPK/ERK pathways leading to upregulation of endothelial NOS and increased NO synthesis [144]. Resveratrol also prevents diabetes-induced impairment of eNOS-dependent vasorelaxation in cerebral arterioles, suggesting an important therapeutic potential of resveratrol in treating cerebrovascular dysfunction in diabetic patients [145]. Several other studies have attributed the protective effects of resveratrol from stroke to its neuroprotective effects [145-150], which have been reviewed

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previously [151]. Although there is no human clinical trial that investigated the protective effects of resveratrol in stroke patients, a single dose of resveratrol has been shown to increase the cerebral blood flow during a performance task in healthy adult subjects [152, 153].

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Myocardial Ischemia and Ischemia-Reperfusion Injury

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Preclinical studies:

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Approximately 15.4 million Americans have coronary heart disease, which makes up more than half of all cardiovascular incidents in people under the age of 75 [2]. According to the WHO, ~7.3 million people died in 2008 due to ischemic heart disease [1]. Myocardial ischemia is caused by an occlusion of one or more of the coronary arteries that results in a decrease in oxygen supply to the myocardium. If the ischemic period lasts for a prolonged period of time then cardiomyocyte death begins and the ischemic episode causes a myocardial infarction (MI) [154]. The prevalence for MI among adults in the United States is 4.2% and an estimated 620,000 Americans will experience a new coronary attack this year [2]. As resveratrol has been shown to protect against ischemic damage and ischemia-reperfusion injury in a variety of noncardiac tissues [142, 143, 155, 156], it is not surprising to find that resveratrol has similar protective effects in the myocardium. Indeed, resveratrol has been shown to protect against myocardial ischemia by inhibiting platelet aggregation, preconditioning muscle tissue to ischemia-reperfusion, and potentially regenerating infarcted tissue [157].

There have been a number of studies investigating the effects of resveratrol in the ischemic myocardium, either examining its protective effect against reperfusion injury or in permanent ligation models of ischemia and infarction (Table 3). For instance, pretreatment with resveratrol has been shown to be cardioprotective against ischemia-reperfusion injury [90, 158164]. In rats with their left main coronary artery ligated [160], preconditioning with resveratrol (1 mg/kg IP) for 60 minutes prior to occlusion had significant benefits following reperfusion including a decreased severity of arrhythmia as well as a dramatically reduced infarct [160]. In another study, 10 μM resveratrol delivered via transjugular injection 15 minutes prior to occlusion in rats, restored systolic pressure and decreased the infarct size following reperfusion [163]. Moreover, resveratrol administration (5 mg/kg IP) to mice 24 hours prior to occlusion decreased infarct size following ischemia-reperfusion [164]. In a hypercholesterolemic rat model, resveratrol (20 mg/kg/day) pretreatment for two weeks was also found to reduce infarct size in isolated hearts following ischemia-reperfusion or in rats that had their left descending coronary artery ligated in vivo [90]. Together, these results highlight the ability of resveratrol to precondition the myocardium to ischemia-reperfusion injury. As mentioned, severe and prolonged myocardial ischemia, results in cell death and infarction. In addition to the beneficial nature of resveratrol in ischemia-reperfusion injury, resveratrol has been proven to be beneficial in models of permanent ischemia. For example, resveratrol has been found to be cardioprotective when given prior to left anterior descending

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(LAD) coronary artery ligation-induced infarction [158, 159, 161]. Specifically, pretreatment with resveratrol (1 mg/kg/day) for two weeks reduced infarct size and improved cardiac function as early as 4 days following the MI [161]. Resveratrol pretreatment (5 mg/kg/day) [158] or (10 mg/kg/day) [159] for one week prior to LAD ligation and continued for an additional three weeks also increased survival, improved contractile function and decreased infarct size [158, 159]. Additionally, resveratrol treatment suppressed ventricular arrhythmias and decreased cardiac hypertrophy [158]. Furthermore, in a porcine model of ischemia, Yorkshire mini-swine treated with resveratrol (100 mg/kg/day) for four weeks prior to the introduction of ischemia with an ameroid constrictor (a device that gradually occludes blood flow) and seven weeks post surgery had improved vascular function [162]. However, in contrast to the previous beneficial studies, Burstein et al. did not observe the same prominent protective role of resveratrol in a rat model of MI [165]. In this instance, the rats were fed resveratrol (17 mg/kg/day) for 13 weeks, one week prior to artery ligation and 12 weeks following the surgery. Although, resveratrol did not improve cardiac function under basal conditions, it did improve cardiac performance under pharmacological stress testing with dobutamine [165]. The reasons for the lack of a pronounced cardioprotective effect of resveratrol following the infarct are currently unknown. Indeed, since the dose and duration of resveratrol in the latter study exceeds those in the other rodent studies, it is difficult to say why they did not see the same beneficial effects as otherwise reported. One potential explanation is that the infarct size varied between the studies. For example, in the study where resveratrol was found to reduce infarct size, infarcts were ~50% (expressed as a fraction of LV area) [158], whereas in the study where no change in infarct size was observed, infarct size was significantly smaller (7%-expressed as a fraction of heart weight). Thus, it is possible that the cardioprotective effect of resveratrol is only evident with larger infarcts [165]. Another explanation is that resveratrol is thought to be less cardioprotective at the higher doses in rodents. In rats fed 2.5 mg/kg/day for 10 days, resveratrol was found to be protective against ischemia-reperfusion injury, whereas higher doses (25 mg/kg/day and 100 mg/kg/day) were not [166]. The ability of resveratrol to protect the heart from ischemia, when administered prior to the ischemic episode, is well established. Perhaps of even more clinical relevance, however, is that resveratrol also prevents cardiac damage when delivered after the insult. For instance, it has been shown that left ventricular systolic/diastolic function improved and infarct size was reduced in rats that received a daily administration of resveratrol 1 mg/kg for four weeks post-MI [167]. In addition, Xuan et al. performed left coronary artery ligation on mice and found that resveratrol (20 mg/kg/day for 42 days) decreased cardiac remodeling and increased survival following the MI [168]. Similar positive results were observed in rats treated with 2.5 mg/kg/day resveratrol for 16 weeks post-MI [169]. In this latter study, resveratrol treated rats had improved cardiac function, decreased mortality, and decreased B-type natriuretic peptide (BNP) serum levels, demonstrating that resveratrol protected against the development of MI-induced heart failure [170]. Finally, two-week treatment with resveratrol (50 mg/kg/day by osmotic pump) commenced four weeks following an MI in mice, improved cardiac performance and morphology [171]. Taken together, it appears that resveratrol may be effective at preventing ischemic damage and infarct expansion following MI.

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In addition to the cardioprotective role of resveratrol, it has also been shown to protect against ischemia-reperfusion injury in other organs as well. Indeed, resveratrol has been shown to protect against ischemia-reperfusion injury in skeletal muscle in an animal model of hind limb ischemia [172, 173]. Similarly, resveratrol has also been shown to protect against ischemiareperfusion injury in ovaries of female rat [155], testes of male rats [156], visceral organs [174], and kidneys [175]. Although the authors of the previous studies have attributed the protective effects of resveratrol to its anti-oxidant and cytoprotective effects in the target organs [155, 156, 172, 173], these protective effects can also be attributed to the well-documented vascular protective effects of resveratrol.

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The ability of resveratrol to protect from myocardial ischemic damage and/or ischemiareperfusion injury is complex and involves numerous mechanisms (Fig. 2). However, a primary mediator appears to be the increased production of the cardioprotective molecule, NO [176]. NO is potent vasodilator and is beneficial in the ischemic myocardium by promoting perfusion of the damaged tissue [50]. Indeed, rats treated with resveratrol prior to ischemia-reperfusion were found to have elevated levels of NO, when compared to rats treated with vehicle [163]. In addition to increasing NO levels, pretreatment with resveratrol has been shown to increase eNOS and nNOS protein levels in the ischemic myocardium compared with the vehicle treated animals [159, 160]. This may help explain the mechanism of resveratrol-mediated protection as independent studies have clearly shown that deficiency of eNOS worsens myocardial ischemiareperfusion injury [177, 178] and its overexpression is cardioprotective [179, 180]. The putative role of NO being a mediator of the cardioprotective effects of resveratrol is also supported by the various studies that have indicated an increase in phosphorylation of eNOS at serine 1177 in the presence of resveratrol [25, 90, 162]. Furthermore, in rats treated with L-NAME (an inhibitor of NOS), resveratrol-dependent recovery of cardiac function was abrogated, suggesting a crucial role of NOS in the protective nature of resveratrol [160, 181]. Overall, these findings suggest that resveratrol is cardioprotective in part through the stimulation of NO production and subsequent vasodilation. In addition to promoting vasodilation, NO is a well-known mediator of angiogenesis [182], and therefore it seems likely that resveratrol may also protect the heart from ischemic damage via this mechanism. While this would only be applicable in chronic ischemia, a number of studies have observed that pretreatment with resveratrol increases myocardial capillary density following MI. In addition to NO stimulation [163] and eNOS activation [25, 90, 162], resveratrol has also been shown to increase expression of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF) and heme oxygenase-1 [90, 159, 161]. However, another study demonstrated that although resveratrol seemed to improve vascular function through increased expression of VEGF and phosphorylation of eNOS, no increase in capillary density was observed [162]. The authors of this latter study provided several explanations for the differences in their study compared to other studies including: 7 weeks following implantation with an ameroid constrictor may not be enough time to observe vessel formation, prolonged Akt activation may inhibit angiogenesis [183], or the potential presence of angiogenic inhibitors not measured in their study, such as endostatin or angiostatin [162]. Finally, the high

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Resveratrol also likely protects the heart from ischemia-reperfusion injury through the reduction in oxidative stress. As the myocardium is reperfused following an acute ischemic episode, the tissue is damaged, in part, by the generation of ROS [188]. Resveratrol has been shown to reduce lipid-peroxidation [163, 189], reduce the levels of superoxide [46, 190], and activate anti-oxidant defense mechanisms [161, 189]. A recent proteomics study on Yorkshire miniswine implanted with an ameroid constrictor identified a number of differences in proteins expressed in the animals pre-treated with resveratrol [191]. One of the proteins that were overexpressed in the animals treated with resveratrol was the radical scavenging protein peroxiredoxin 2. Therefore, it seems likely that resveratrol also protects the reperfused ischemic heart by minimizing damage resulting from ROS.

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In addition to the importance of vasodilation, reduced oxidative stress, and vessel formation, the activation of AMPK and/or SIRT1 by resveratrol to trigger autophagy in the cardiomyocyte has been identified as a potential protective mechanism. In H9c2 cells, resveratrol was found to reduce cell death induced by H2O2 through activation of AMPK [190]. Furthermore, pretreatment of H9c2 cells with resveratrol prior to anoxia/re-oxygenation, reduced cell death in an AMPK and autophagy-dependent manner. Resveratrol was also shown to be protective in cardiomyocytes exposed to anoxia/reoxygenation through inhibition of fractalkine (FKN) [168], which was shown to inhibit the resveratrol-enhancement of autophagy in cardiomyocytes [168]. The roles of FKN and autophagy are important as it has been shown that autophagy is beneficial following MI due to a correction of the myocardial energy imbalance [192]. In rats exposed to ischemia-reperfusion, low doses of resveratrol induced autophagy and decreased apoptosis in the myocardium and protected against ischemia-reperfusion induced impairment in cardiac function [166]. AMPK-dependent activation of autophagy was also correlated to the beneficial effects of resveratrol in a mouse hearts following MI and inhibition of autophagy worsened cardiovascular function [171]. In addition to the role of AMPK, SIRT1 has been implicated in the ability of resveratrol to promote autophagy. For instance, in a MI model in rats, resveratrol increased SIRT1 and AMPK expression, and in vitro studies indicated that inhibition of SIRT1 decreased AMPK levels [169]. Moreover, in mice pretreated with resveratrol, a decrease in infarct size coupled with an increase in deacetylated substrate (indicating SIRT1 activation) was observed following ischemia-reperfusion [164]. Additionally, mice pretreated with sirtinol (a SIRT1 inhibitor) almost entirely abolished the beneficial effects of resveratrol [164], and prevented autophagy in vitro [193], which strongly supports the integral role of SIRT1-activation in mediating some of the effects of resveratrol. Overall, these studies show that resveratrol functions by a variety of mechanisms to protect the heart from damage following ischemia, ischemia-reperfusion, and myocardial infarction. The primary mechanisms appear to involve a decrease in oxidative stress, and an increase in vasodilation, angiogenesis, and autophagy.

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The effect of resveratrol in patients with ischemic heart disease has been investigated in a few clinical trials. Oral administration of resveratrol, calcium fructoborate (CF), and their combination was shown to improve several markers in patients with stable angina pectoris [194]. CF is a naturally occurring mixture of calcium, fructose and boron found in fruits, vegetable, herbs and wine and may have its own anti-inflammatory properties [195]. Furthermore, since CF has been shown to stabilize resveratrol in the digestive tract [194], it may enhance the effects of resveratrol. This study was randomized, double-blinded, activecontrolled and paralleled with three groups. In total, 116 patients were split into four groups: 29 patients in control group, 29 patients receiving 20 mg/day resveratrol, 29 patients treated with 20 mg/day resveratrol and 112 mg/day CF, and 29 patients receiving 112 mg/day CF. The study was conducted for 60 days, throughout which time patients continued to receive normal therapy. Dramatic reductions in high-sensitivity C-reactivity protein (a biomarker of inflammation) and BNP (a biomarker of cardiac dysfunction) were observed for all three groups, with the largest reductions occurring in the CF group and the CF and resveratrol groups. Lipid profiles (LDL and HDL cholesterols and triglycerides) were also slightly improved across the treatment groups. Importantly the subjects’ quality of life (defined by angina episodes/week, weekly nitroglycerin consumption, and improvement in angina class) was also dramatically improved across the treatment groups, with the largest gains observed in the combined CF + resveratrol group. A limitation of the study is that while the authors suggest that CF stabilizes, and therefore improves the bioavailability of resveratrol, plasma levels were not measured to confirm this. Nevertheless, it seems that the combination of resveratrol with CF had beneficial effects and improved the quality of life of patients with stable angina pectoris. There has also been a clinical study focusing on the effects of resveratrol in a grape extract on patients with CAD (stable angina or acute coronary syndrome) [196]. This study was a three-arm parallel, randomized, triple-blind, placebo-controlled trial that occurred over the course of 1 year with patients with stable CAD receiving either placebo, a conventional grape extract (GE), or a grape extract containing resveratrol (GE-resveratrol). In this case, the trial compared placebo (25 patients) with grape extract (25 patients) and grape extract containing resveratrol (25 patients). Patients received 350 mg/day (in the GE-resveratrol, 8 mg resveratrol) for the first six months of the study and 700 mg/day (16 mg resveratrol) for the next 6 months. The patients receiving GE-resveratrol had increased levels of the anti-inflammatory adipokine, adiponectin, and a reduction in the thrombogenic plasminogen activator inhibitor type 1 (PAI-1), suggesting that resveratrol may be cardioprotective, since increasing adiponectin [197] and/or decreasing PAI-1 [198] has been proposed to be a promising therapy for CAD. Moreover, there was a down regulation of pro-inflammatory genes expressed in peripheral blood mononuclear cells (PBMCs) in the GE-resveratrol group. The atherogenic lipid load decreased in both grape extract groups, demonstrating that there may be other beneficial components in the Grape Extract. Consistent with the previous clinical trial, these data point towards the potential of resveratrol a treatment of CAD.

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There has also been a clinical study examining the effects of resveratrol treatment in patients who have had an MI [199]. This double blind, placebo controlled, randomized study included 40 Caucasian patients (26 men and 14 women with a mean age of 66.3 years) studied over the course of 3 months. The patients received either placebo or 10 mg/day resveratrol in conjunction with standard medication over the course of the treatment. In patients treated with resveratrol, diastolic function was significantly improved with a modest increase in systolic function, endothelial function was improved, red blood cell deformability was increased, platelet aggregation was inhibited (with increased sensitivity to aspirin), and LDL cholesterol levels were decreased. Although we do not know if there is a direct effect of resveratrol on the cardiomyocytes in these patients, it seems at least that resveratrol mediates its effects in this patient cohort via improved vascular function and/or preventing negative consequences associated with atherosclerosis. As such, this finding suggests that resveratrol treatment of post-MI patients, when given in conjunction with other prescribed therapeutic agents, may be a promising approach to lessen the risk of secondary MI.

Cardiac Hypertrophy and the Pathogenesis of Heart Failure

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Heart failure is a clinical syndrome that arises from a variety of pathophysiologies including, hypertension, MI, and congenital cardiomyopathies [200]. Heart failure can also be caused by diabetic cardiomyopathy [201], chemotherapeutic agents [202, 203], rheumatic valve disease, Chagas’ disease, and endomyocardial valve disease [200]. Heart failure is defined as the inability of the heart to supply the body’s organs and tissues with enough oxygen and nutrients to meet its metabolic demands. The goals of treatment of heart failure includes stabilizing the symptoms and reversing myocardial dysfunction using common treatments such as beta-blockers, diuretics, renin-angiotensin-aldosterone inhibitors, vasodilators, and/or positive inotropes [204]. Despite these treatments, heart failure remains a debilitating disease with a poor prognosis [200, 205]. In fact, in the United States, roughly 1 in 9 deaths are caused by heart failure [2], demonstrating the clinical burden of this syndrome. The natural response of a decrease in heart function is cardiac remodelling such that function can be maintained. This myocardial remodelling involves numerous processes [206] including cardiac hypertrophy, which is characterized by an increase in cardiomyocyte size [205]. In the short-term, cardiac hypertrophy is compensatory but often progresses to a maladaptive form of hypertrophy that eventually contributes to poor contractile performance [205]. Indeed, the hypertrophied heart consumes more energy and is stiffer that the healthy heart [205] and the maladaptive hypertrophy ultimately impairs systolic and diastolic function. These changes can contribute to the pathogenesis of heart failure and/or worsen existing heart failure [157]. Since pathological cardiac hypertrophy leads to heart failure, the ability to prevent, arrest, or even reverse this process may have important therapeutic potential [205].

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In order to screen for effective treatments of heart failure, a number of animal models have been developed in an attempt to mimic the development of human heart failure [207]. Resveratrol has been investigated in a number of these models including pressure-overload [208-210], volume overload [210], SHRs [30, 32], doxorubicin-induced cardiotoxicity [202, 203] (see section on chemotherapy-induced cardiotoxicity), MI, ischemia-reperfusion injury [168, 169, 171], myocarditis [211], and a TO-2 hamster model of heart failure [212] (Table 4). Many studies using resveratrol in these models focus on the ability of resveratrol to prevent cardiac hypertrophy and/or prevent cardiac dysfunction leading to heart failure as opposed to testing resveratrol as a heart failure treatment per se. Notwithstanding this fact, cardiac hypertrophy and cardiac dysfunction are extremely important in the pathogenesis of heart failure and these studies still have significant value.

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Pathological stress, such as increased load on the heart or cardiomyopathies that alter the contractile function of the heart, typically leads to cardiac hypertrophy [205]. As has been discussed, the ability to reduce hypertension and reduce cardiac afterload also predictably prevents cardiac hypertrophy [213]. Indeed, there have been a number of studies that have indicated that resveratrol is capable of preventing and reversing cardiac hypertrophy caused by hypertension (Table 4) [25, 28, 30, 32, 33, 210, 214, 215]. While many of the hypertension studies suggested that the reduction in BP contribute to the improvement in cardiac hypertrophy, several other studies have indicated that resveratrol can reduce cardiac hypertrophy even in the absence of a decrease in BP. For instance, in the SHR, low doses of resveratrol (2.5 mg/kg/day) prevented cardiac hypertrophy without reducing BP [30, 32]. Furthermore, resveratrol reduced cardiac hypertrophy in surgical models of increased afterload [208-210], which are mechanically confined to elevated afterloads. Additionally, resveratrol has been shown to prevent/treat heart failure in models where elevated afterload is not the cause of hypertrophy, such as in the TO-2 hamster model of heart failure [212], in the experimental model of autoimmune myocarditis [211], in a number of rodent models of infarction [158, 167169, 171], and in isolated cardiomyocytes [216]. Together, these results imply that resveratrol can prevent cardiac hypertrophy and dysfunction through cardiomyocyte autonomous effects and not solely from a more general mechanism of reduced BP [4, 157]. The ability of resveratrol to prevent cardiac hypertrophy and the development of cardiac dysfunction has also been investigated in several surgical models that initiate cardiac hypertrophy and can progress to heart failure. Interestingly, resveratrol did not prevent cardiac dysfunction and remodelling in a volume-overload model of cardiac hypertrophy [210]. However, in an aortic-banded pressure-overload model of hypertension, resveratrol (2.5 mg/kg/day) treatment prevented both cardiac hypertrophy and cardiac dysfunction [210]. Recently, Gupta et al. used transverse aortic constriction (TAC)-induced pressure-overload model of cardiac hypertrophy in mice to study the effects of resveratrol [209]. In that study, mice receiving 10 mg/kg/day resveratrol following the TAC surgery displayed significantly reduced pathological cardiac remodelling and dysfunction as well as reduced oxidative stress, inflammation, fibrosis and apoptosis [209]. Moreover, resveratrol treatment in an aortic-banded

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pressure-overload model of cardiac hypertrophy in rats prevented and reversed hypertrophy [208, 210]. Two weeks following surgery, rats were administered resveratrol (2.5 mg/kg/day) for a total of four weeks. Following the treatment period, resveratrol improved contractile function and inhibited the development of hypertrophy, specifically concentric remodelling [208]. The ability of resveratrol to prevent cardiac hypertrophy was also investigated in the Dahl-salt sensitive (DSS) rat [217]. Rats were fed a high-salt diet for 3 weeks and then treated with resveratrol (18 mg/kg/day in diet) for an additional 8 weeks. Following the initial three-week period prior to resveratrol treatment, BP and cardiac hypertrophy had increased in the high salt treated rats. Interestingly, resveratrol treatment increased survival rate, preserved myocardial function, prevented endothelial dysfunction and muscle mitochondrial respiration, without decreasing BP [217]. These studies indicate that resveratrol is able to restore cardiac structure and function following the development of hypertrophy and therefore seems to be able to reverse the early development of processes involved in the progression to heart failure.

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In many of the aforementioned studies, resveratrol was administered prior to the development of heart failure. Indeed, there have been a number of studies demonstrating that resveratrol can prevent cardiac hypertrophy, improve cardiac function and impede the progression of heart failure following cardiac damage [158, 167-169, 171], and thus implicate resveratrol as a treatment for heart failure. However, many of these previous studies are prevention studies and less work has been published showing that resveratrol has beneficial effects in animals with established heart failure. However, Kanamori et al. addressed this by examining the outcomes of mice with established MI-induced heart failure following treatment with resveratrol [171]. In that study, MI was induced in mice via left coronary artery occlusion, and resveratrol treatment was commenced 4 weeks after the surgery at a time when left ventricle ejection fraction (LVEF) was significantly reduced (~39% versus ~74% in the sham animals) and animals displayed signs of heart failure. Of importance, following 2 weeks of treatment with resveratrol (50 mg/kg/day), LVEF improved from ~39% to ~47% likely due to a decrease in the size of infarct and a reversal of the maladaptive remodelling [171]. This study is particularly exciting as it suggests that resveratrol may be an effective treatment for heart failure by preventing infarct expansion. However, whether this is relevant in humans with established heart failure occurring from previous MI’s where the scar has typically already been formed is currently unknown. In addition, it is unknown if resveratrol can be used as a treatment for heart failure in non-ischemic models of heart failure. There are several central mechanisms by which resveratrol imparts its anti-hypertrophic and cardioprotective affects including: reduction of oxidative stress, inhibition of protein synthesis, improved Ca2+-cycling and inhibition of hypertrophic gene expression (Fig. 3). Oxidative stress is an important trigger of heart failure [218] and is correlated with an increase in severity of heart failure [188]. Oxidative stress has also been shown to lead to cardiac hypertrophy [219]. One anti-oxidant mechanism by which resveratrol may mediate its beneficial effects in heart failure pathogenesis is by increased expression of SOD2. In the TO-2 hamster heart, resveratrol enhanced cardiac SOD2 expression in a SIRT1-dependent manner and reduced ROS [212]. Similarly, SOD2 activity and levels of the ROS scavenger, glutathione, were increased by resveratrol in TAC mice when compared to TAC mice treated with vehicle

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[209]. On the other hand, in an MI model of cardiac hypertrophy, the expression level of SOD2 was unaltered by resveratrol [171], suggesting that SOD2 up-regulation may not be the main anti-oxidant mechanism of resveratrol. Furthermore, although resveratrol was found to reduce oxidative stress (in the form of thiobarbituric acid reactive substances) in both pressure-overload and volume-overload models of cardiac hypertrophy, it was only beneficial in the pressureoverload model of cardiac hypertrophy [210]. This implies that the ability of resveratrol to inhibit hypertrophy may not be directly mediated by its anti-oxidant effects. Another possibility is that oxidative stress may play a different role in the development of concentric hypertrophy (pressure-overload) versus eccentric hypertrophy (volume-overload) [210]. Lastly, in addition to the anti-oxidant nature of resveratrol, its activation of eNOS may play an important role in slowing the development of cardiac hypertrophy [208]. Indeed, Juric et al. found both eNOS and iNOS levels were reduced upon aortic banding, and resveratrol partially restored their levels [208]. They hypothesized that the anti-hypertrophic effect of resveratrol, may in-part be the result of elevated NO, which has been shown to have both cardioprotective and antihypertrophic properties [220]. Consistent with this, resveratrol was shown to increase serum NO levels in a partially nephrectomised model of hypertrophy [214]. Together, these data suggest that resveratrol may protect against cardiac hypertrophy through an anti-oxidant dependent mechanism and/or NO production.

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One of the hallmarks of cardiac hypertrophy is enhanced protein synthesis [221]. Protein synthesis can be regulated by numerous proteins including ones that control protein translation such as including eukaryotic elongation factor-2 (eEF2) and p70S6 Kinase (p70S6K) [222]. In hypertrophic cardiomyocytes, resveratrol has been shown to inhibit phenylephrine-induced cardiomyocyte hypertrophy by inhibiting p70S6K and eEF2 through AMPK activation and Akt inhibition [216]. Likewise, resveratrol has also been shown to prevent hypertrophy induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in H9c2 cells [223]. Although Akt plays a role in the development of cardiac hypertrophy [224, 225], since the anti-hypertrophic effects of resveratrol was not lost in Akt1/2 null mouse embryonic fibroblasts (MEFs) [216], it is unlikely that Akt inhibition is the mechanism by which of resveratrol prevents cardiac hypertrophy. On the other hand, AMPK activation seems to be essential for the anti-hypertrophic effects of resveratrol, since resveratrol was less effective at inhibiting hypertrophic signalling in AMPK null MEFs [216]. Moreover, the anti-hypertrophic effect of resveratrol was abolished by the AMPK inhibitor, compound C [226], and although resveratrol treatment of SHR or Ang II infused mice activated AMPK, no inhibition of Akt was observed [25, 30, 226]. Additionally, in a MI model of heart failure progression, although resveratrol had a pronounced activation of AMPK, no change in Akt phosphorylation was observed [171]. Together, these findings suggest that resveratrol inhibits cardiac hypertrophy via AMPK-dependent pathways. Of importance, although AMPK activation by resveratrol has been suggested to mediate its anti-hypertrophic effects by reducing protein synthesis, activation of AMPK also stimulates autophagy, which has been shown to also cause a decrease in cardiac hypertrophy [192]. Since it has been shown that resveratrol induces autophagy [168, 171, 193], it seems likely that this too plays a role in resveratrolmediated inhibition of cardiac hypertrophy and further research in this area is warranted.

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Although resveratrol activates numerous molecular signalling pathways [227], the activation of AMPK appears to be an extremely important mediator of many of the beneficial effects of resveratrol in the cardiomyocyte [4, 228]. One potential mechanism by which resveratrol leads to AMPK activation is via preventing 4-hydroxy-2-nonenal (HNE)-mediated inhibition of LKB1 (the upstream kinase of AMPK) [25, 30]. HNE is an electrophillic lipid peroxidation by-product that is formed during hypertrophy and inhibits LKB1 through the formation of covalent adducts. LKB1 inhibition leads to a decrease in AMPK phosphorylation and an increase in cardiomyocyte hypertrophy [30]. Resveratrol has been shown to block HNEadduct formation on LKB1 and rescue AMPK activity in cardiomyocytes, SHR, and Ang II infused mice [25, 30]. These data lend support to the argument that the anti-hypertrophic effects of resveratrol are mediated through its activation of AMPK. Consistent with the involvement of LKB1 in regulating cardiac hypertrophy, SIRT1 has been shown to deacetylate and potentially activate LKB1 [59] and may be another mechanism by which resveratrol activates AMPK.

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Of importance to the regulation of cardiac hypertrophy and the activation of AMPK, resveratrol-induced activation of SIRT1 is associated with a reduction in cardiac hypertrophy [229]. For example, in the rat model of myocarditis, resveratrol treatment caused a substantial increase in SIRT1 expression levels [211]. Likewise, in an MI model of heart failure, rats treated with resveratrol had improved cardiac function and enhanced SIRT1 levels [169]. Furthermore, in a diabetic model of cardiomyopathy in mice, resveratrol was shown to activate SIRT1, promote autophagy, and prevent hypertrophy [193]. In the same study, SIRT1 inhibition eliminated the resveratrol-mediated enhancement of autophagy in H2O2-treated H9c2 cells, suggesting that SIRT1 plays an important role in the anti-hypertrophic effects of resveratrol [193]. While it has been shown that at higher concentrations, resveratrol is able to activate AMPK independent of SIRT1, the beneficial effects of resveratrol on mitochondrial function have been attributed to a SIRT1-dependent mechanism [59]. However, the involvement of SIRT1 as a mediator of the anti-hypertrophic effects of resveratrol is not completely agreed upon. For instance, it has been proposed that SIRT1 activation promotes cardiac hypertrophy through its deacetylation and activation of Akt [230]. This is in agreement with mouse models showing that high levels of SIRT1 expression results in enhanced cardiomyocyte growth [231], and low SIRT1 expression prevents hypertrophy [230], implying that SIRT1 activation by resveratrol would lead to hypertrophy. As such, the role that resveratrol-mediated SIRT1 activation plays in the development of cardiac hypertrophy has yet to be clearly established. Since intracellular Ca2+ cycling determines contractility in normal and failing hearts [232], the effects of resveratrol on Ca2+ handling may be implicated in its protective effects in heart failure. Interestingly, resveratrol has also been shown to improve cardiac function in diabetic mice through increasing sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (SERCA2a) expression in a SIRT1-dependent mechanism [233]. Similarly, resveratrol restored SERCA2 promoter activity in a SIRT1-dependent mechanism in primary cardiomyocytes cultured in high glucose medium [233]. However, in a DSS rat model of heart failure, resveratrol treatment did not significantly increase SERCA2 expression levels [217], suggesting that the effect of resveratrol on SERCA2 and Ca2+ homeostasis may be model-dependent. Although the effect

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on SERCA2 may still need to be clarified, another mechanism that has been proposed for AMPK activation by resveratrol is through activation of calcium/calmodulin-dependent kinase kinase 2 (CamKK2) via an increase in intracellular Ca2+ levels through phoshpholipase C and the ryanodine receptor Ca2+-release channel [234]. Importantly, this mechanism was identified in the skeletal-muscle derived C2C12 cell line, and confirmation of this mechanism in cardiomyocytes is still necessary. Nevertheless, polydatin, a resveratrol glucoside, has been shown to up-regulate the activity of ryanodine receptors and increase myofilament Ca2+ sensitivity resulting in an increase of cardiomyocyte contractility [235]. Therefore, further research is needed to investigate whether resveratrol can up-regulate the activity of ryanodine receptors in cardiomyocytes, and whether this effect may be another cardioprotective mechanism of resveratrol in heart failure.

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Finally, activation of fetal gene expression is another hallmark of cardiac hypertrophy. Although a variety transcription factors are involved in this switch [206], the nuclear factor of activated T-cell (NFAT) also plays a role [206]. NFAT is a Ca2+-dependent transcription factor, which exist in the cytoplasm in its phosphorylated state. Calcineurin dephosphorylates NFAT thus allowing NFAT to translocate into the nucleus where it promotes the transcription of a number of genes that encode for proteins involved in promoting cardiac hypertrophy [236]. As such, the calcineurin-NFAT pathway has been identified as a target for agents designed to inhibit cardiac hypertrophy [205, 206]. Of importance, resveratrol inhibits NFAT in neonatal rat cardiomyocytes treated with phenylephrine [216] via an AMPK-mediated pathway and prevents cardiomyocyte growth. This finding is consistent with an in vivo study showing that another activator of AMPK also depressed NFAT signaling and attenuated cardiac hypertrophy in a pressure overload rat model [237]. Thus, the findings with resveratrol indicate that resveratrol may prevent cardiac hypertrophy through inhibition of protein synthesis and inhibition of the NFAT pro-hypertrophic genetic program. Clinical Studies:

Although the anti-hypertrophic nature of resveratrol is well characterized in vitro and in animal models, it is yet to be studied in patients. To the best of our knowledge, there are no publications involving the effects of resveratrol treatment in patients diagnosed with heart failure. In addition, in the clinical study that tested the effectiveness of resveratrol in the treatment of patients post-MI (discussed in ischemia-reperfusion section), cardiac morphology was not reported and the effectiveness of resveratrol in reversing cardiac hypertrophy in humans has not been reported [199]. However, in that same study, cardiovascular function was examined and it was reported that patients treated with 10 mg/day of resveratrol had significantly improved diastolic function and a modest increase in systolic function [199]. As such, these data suggest that resveratrol may be effective in the treatment of MI-induced cardiac dysfunction.

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ACCEPTED MANUSCRIPT Diabetic Cardiomyopathy

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Several studies have shown that diabetes is an independent risk factor for heart failure, even after corrections for other confounding variables such as CAD, hypertension, dyslipidemia, and obesity [238, 239]. The term “Diabetic Cardiomyopathy” has been introduced to describe the decline in cardiac function secondary to diabetes [240]. Diabetic cardiomyopathy is usually associated with early diastolic dysfunction, late systolic dysfunction, increased interstitial fibrosis, cardiomyocyte hypertrophy, increased oxidative stress, increased apoptosis, and abnormal cardiac energy metabolism [201, 241, 242]. Since resveratrol has been shown to possess anti-hypertrophic, anti-apoptotic, and anti-oxidant properties in cardiomyocytes [58, 216], it may target several pathophysiologic events implicated in the pathogenesis of diabetic cardiomyopathy. In addition to these direct cardioprotective effects, resveratrol has also been shown to improve insulin sensitivity in animal models of diabetes [243] and metabolic syndrome [244]. Indeed, resveratrol has been shown to protect against diabetic cardiomyopathy in several preclinical studies due to both direct cardioprotective effects and systemic anti-diabetic properties [245], thus widening the scope of the potential therapeutic use of resveratrol.

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Resveratrol treatment has been shown to improve the cardiac function in streptozocininduced diabetic rats and mice (a model of type 1 diabetes) in several studies (Table 6). In streptozocin-induced diabetic rats, resveratrol has been demonstrated to significantly reduce blood glucose levels in treated diabetic rats as compared to non-treated diabetic rats [246]. Importantly, resveratrol-treated diabetic rats demonstrated significant improvement of LV function as compared to non-treated diabetic animals [246]. In addition, when subjected to an ischemic injury, resveratrol treatment resulted in significantly reduced infarct size [246]. These protective effects were associated with an increase in p-Akt, p-eNOS, Trx-1, heme oxygenase1, VEGF, and SOD in the hearts of resveratrol-treated rats [246]. Interestingly, the administration of L-NAME abrogated most of the cardioprotective effects of resveratrol, suggesting that these protective effects are NO-dependent [246]. Although this study clearly demonstrates the protective effects of resveratrol against diabetic cardiomyopathy, it is not clear whether these effects were due to direct cardioprotective effects of resveratrol on the cardiomyocytes, or secondary to improved glycemic control by resveratrol. Indeed, in the same model of streptozocin-induced diabetes, resveratrol has been found to enhance the glucose transporter GLUT-4 translocation through AMPK/Akt/eNOS signaling pathway in an insulinindependent mechanism in hearts of the diabetic rats [247], suggesting that GLUT-4 translocation and enhanced glucose uptake into to the cardiomyocytes may be involved in the protective effects of resveratrol against diabetic cardiomyopathy. Of particular interest, resveratrol-induced glucose uptake was also observed in cultured H9c2 cardiomyoblasts [247], suggesting a direct effect of resveratrol on the cells. In addition, AMPK activation has been shown to increase insulin sensitivity in insulin-resistant cardiomyocytes [248]. Since resveratrol is known to activate AMPK in cardiomyocytes [216], AMPK activation is likely to mediate the protective effects of resveratrol by both insulin-independent and insulin-dependent mechanisms. Together, these data suggest that the ability of resveratrol to improve the cardiac function in diabetes may be multifactorial and includes both NO-dependent and glucose-dependent effects.

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In addition to the aforementioned mediators of the beneficial effects of resveratrol in diabetes, resveratrol has also been shown to increase survival, improve cardiac function, and decrease interstitial fibrosis in streptozocin-induced diabetic mice through increasing SERCA2a expression [233]. Of interest, resveratrol restored SERCA2 promoter activity in primary cardiomyocytes cultured in high glucose medium [233], suggesting that the cardioprotective effect of resveratrol is not completely dependent on its systemic anti-diabetic properties. In another study, resveratrol treatment has been shown to normalize free fatty acid oxidation, enhance glucose utilization, and reduce biomarkers of oxidative stress in the hearts of streptozocin-induced diabetic rats [242]. Similarly, resveratrol treatment was found to improve the cardiac function in streptozocin-induced type 1 diabetic rats, at least in part, through preserving the functional abilities of cardiac stem/progenitor cells [249]. Moreover, in streptozocin-induced diabetic mice, both low (60 mg/kg/day) and high (300 mg/kg/day) dose resveratrol treatment improved cardiac function, ameliorated oxidative injury, and reduced apoptosis in the hearts of treated diabetic mice [250]. The authors have attributed these effects to the resveratrol-enhanced autophagic reflux in a SIRT1-dependent mechanism [250]. Of importance, the improvement of cardiac function was associated with a dose and timedependent accumulation of resveratrol metabolites, resveratrol-3-sulfate and resveratrol-3glucuronide, in the hearts of streptozocin-induced diabetic rats [251]. Taken together, resveratrol has been shown to protect against diabetic cardiomyopathy in animal models type 1 diabetes through several mechanisms, including those independent from the systemic antidiabetic effects of resveratrol.

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In addition to type 1 diabetes, resveratrol has also been shown to improve cardiac function in animal models of type 2 diabetes. In Leprdb type 2 diabetic mice, resveratrol ameliorated the diastolic dysfunction observed in diabetic mice [252]. This protective effect was attributed to a decrease in oxidative/nitrative stress and an increased NO availability, through inhibition of TNFα-induced NG-κB activation [252]. Although the effect of resveratrol on blood glucose levels was not reported in this study, a separate study in Leprdb mice [253] reported that resveratrol did not alter body weight or reduce hyperinsulinemia or hyperglycemia, further supporting the notion that the protective effects of resveratrol against diabetic cardiomyopathy can occur independently from its systemic metabolic effects. In agreement with this, in a streptozocin-nicotinamide model of type 2 diabetes, resveratrol has been shown to improve LV developed pressure and coronary flow through alleviating the reduction of cardiac antioxidant enzyme activities, reducing cardiac oxidative stress, decreasing apoptosis rate, and inhibiting NF-κB activity [254]. In agreement with the role of oxidative stress in the pathogenesis of diabetic cardiomyopathy, hyperglycemia has been shown to induce oxidative stress by NADPH oxidase in cultured adult rat cardiomyocytes [255]. Of interest, Balteau et al. have shown that AMPK activation reduced ROS production and protected against cardiomyocyte glucotoxicity [256]. Therefore, AMPK activation by resveratrol may protect against diabetic cardiomyopathy by reducing oxidative stress. Moreover, in a Zucker Diabetic Fatty (ZDF) rat model of type 2 diabetes, resveratrol has been shown to prevent mitochondrial dysfunction that preceded the development of diabetic cardiomyopathy [257]. Together, these studies show that resveratrol can also protect against diabetic cardiomyopathy in models of type 2 diabetes.

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Chemotherapy-induced Cardiotoxicity

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In addition to these promising preclinical studies, resveratrol has been shown to improve insulin sensitivity, improved glycemic control, reduce oxidative stress, and activate the Akt pathway in type 2 diabetic patients [74, 75, 258]. Consistent with this, a recent meta-analysis of 11 randomized clinical trials has demonstrated that resveratrol significantly improves glycemic control and insulin sensitivity in diabetic patients [259]. Interestingly, although resveratrol has been shown to provide the most pronounced cardiovascular benefits in clinical trials that enrolled patients with type 2 diabetes [74, 75], there is still no clinical data about the protective effect of resveratrol against diabetic cardiomyopathy. Since diabetic cardiomyopathy develops late after the diagnosis of diabetes [260], long-term clinical trials are warranted to evaluate the effect of resveratrol in diabetic cardiomyopathy.

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Several chemotherapeutic agents (e.g. doxorubicin, sunitinib, cisplatin, and trastuzumab) have been demonstrated to cause severe acute and chronic cardiotoxic effects that may lead to cardiac dysfunction and heart failure [202, 203]. A number of studies have demonstrated that resveratrol protects against doxorubicin-induced cardiotoxicity in a variety of animal models (Table 5) [261-266]. Multiple mechanisms have also been proposed to explain the protective effect of resveratrol against doxorubicin-induced cardiotoxicity. Since ROS generation has been shown to be a major contributor to doxorubicin-induced cardiotoxicity [267], several studies have attributed the cardioprotective effects of resveratrol to its ability to induce endogenous anti-oxidant enzymes such as SOD [262, 263, 268-270], catalase [263, 268, 270], NADPH quinine-oxidoreductase-1 [268], and heme oxygenase-1 [271]. In addition, resveratrol has also been shown to protect against doxorubicin-induced cardiotoxicity through activation of AMPK [272], inhibition of p70S6K-mediated autophagy [273], and activation of SIRT1 [269, 274]. We have also shown that resveratrol can protect against doxorubicin-induced cardiotoxicity by increasing the expression of SERCA2a, mitochondrial electron transport chain complexes, mitofusin-1, and mitofusin-2 [262]. Since resveratrol protects against doxorubicininduced cardiotoxicity through multiple mechanisms, not only through its anti-oxidant properties, resveratrol may be a better candidate to protect against doxorubicin-induced cardiotoxicity in cancer patients than some other anti-oxidant compounds that failed to offer such protection in clinical trials [275]. Although very promising effects have been achieved with resveratrol in animal models of doxorubicin-induced cardiotoxicity, there is much less research into the protective effects of resveratrol against cardiotoxicity caused by other chemotherapeutic agents. Wang J et al have shown that resveratrol alleviated cisplatin-induced myocardial damage in a dose-dependent manner demonstrated by an improvement in histological appearance of the myocardium and normalization of markers of myocardial damage such as creatine kinase (CK) and lactate dehydrogenase (LDH) [270]. Resveratrol has also been shown to protect against arsenic trioxide-induced cardiotoxicity in mice and rats [276, 277]. The protection against cisplatin and arsenic trioxide-induced cardiotoxicity has been attributed to the increase in the endogenous

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anti-oxidant enzymes activity namely, SOD, catalase, and glutathione peroxidase [270, 277], in addition to activation of the anti-oxidant NRF2-heme oxygenase-1 pathway [276], suggesting the importance of the anti-oxidant properties of resveratrol in these models as well. Recently, an in vitro study has reported that resveratrol protects against sunitinib-induced hypertrophy in H9c2 cells [278]. The authors of that study proposed that resveratrol prevents hypertrophy by antagonizing the aryl hydrocarbon receptor (AhR) and inhibiting CYP1A1 enzyme [278], suggesting that resveratrol may also protect against chemotherapy-induced cardiomyopathy through its AhR-antagonistic properties. The translational potential of these findings is very promising, since resveratrol has also been shown to augment the chemotherapeutic activity of several anti-cancer agents including doxorubicin [265, 279, 280]. Nevertheless, there is very limited information about the cardioprotective effects of resveratrol in cancer patients treated by doxorubicin or other cardiotoxic chemotherapeutic agents.

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Cardiac arrhythmia remains a serious medical problem despite intensive research in this area [281]. For instance, atrial fibrillation (AF), which is the most common cardiac arrhythmia, remains a significant risk factor for stroke, heart failure, and cardiovascular-related mortality [282]. Despite the availability of a number of anti-arrhythmic medications, the safety profile of most of them is far from optimum [283]. Therefore, the discovery that resveratrol also possessed anti-arrhythmic properties is important for the clinical utility of resveratrol. That said, the anti-arrhythmic effect of resveratrol is not as well-studied. The studies that have been performed show that a single IV dose of resveratrol (5, 15, 45 mg/kg) caused a significant antiarrhythmic effect in three models of arrhythmia: aconitine-induced, ouabain-induced, and coronary ligation-induced arrhythmias [284]. In the coronary ligation-induced arrhythmia model, the anti-arrhythmic effect of the highest resveratrol dose was comparable to that of lidocaine, a known anti-arrhythmic drug [284]. Similarly, resveratrol suppressed ischemia-reperfusioninduced ventricular arrhythmia in a Langendorff-perfused rat heart [285]. Lastly, chronic oral resveratrol treatment (5 mg/kg/day for 4 weeks starting one week before MI) significantly suppressed MI-induced ventricular tachycardia and ventricular fibrillation and improved acutephase survivals in rats following MI [158]. Several in vitro studies have demonstrated the electrophysiological properties of resveratrol. The anti-arrhythmic effect of resveratrol has been attributed to Ca2+ channel antagonism and KATP channel opening [158]. Other studies have shown that resveratrol significantly shortened action potential duration and the peak L-type Ca2+ current in guinea-pig ventricular myocytes [284, 286]. Zhang et al have attributed the inhibition of L-type Ca2+ channels by resveratrol to the inhibition of protein tyrosine kinase in rat cardiomyocytes [287]. On the other hand, Chen et al have shown that resveratrol prolonged action potential duration, inhibited inward sodium and calcium currents, and increased cardiac refractory period [285]. Qian et al have demonstrated that resveratrol inhibited H2O2-induced augmentation of late sodium current in rat ventricular myocytes [281]. Similarly, Li et al have shown that resveratrol

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inhibits oxidative stress-induced arrhythmogenic activity in rabbit ventricular myocytes through inhibition of late Na+ current and L-type Ca2+ current [288]. Of interest, resveratrol inhibited delayed after depolarization induced by ouabain in guinea pig papillary muscle independently from its NO or estrogen-modulating effects [289], suggesting that the anti-arrhythmic properties of resveratrol may be distinct from its other cardioprotective effects. To optimize the antiarrhythmic potential of resveratrol, a new resveratrol derivative has also been shown to be a multi-functional molecule that targets key pathways involved in the pathogenesis of atrial fibrillation [282]. To the best of our knowledge, there are no human studies that investigated the anti-arrhythmic effect of resveratrol.

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Discussion

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Herein, we have reviewed a variety of CVDs and have discussed how resveratrol has been shown to alter their pathophysiology. In general, preclinical studies have yielded promising and in some cases, exciting results for the prevention and/or treatment of hypertension, ischemia-reperfusion, MI, stroke, arrhythmia, dyslipidemia, cardiac hypertrophy, and heart failure. However, treatment and/or prevention of most diseases in animals do not always translate to human studies, so care should be taken in the interpretation of the effectiveness of resveratrol in treating humans with CVD. Indeed, clinical studies involving resveratrol are either inconsistent or not as promising as the preclinical findings reviewed herein. While several positive clinical studies have been published [74-76, 199], other recent clinical studies have refuted the beneficial effects of resveratrol for the treatment of certain cardiovascular disorders [78, 139, 290]. Importantly, a prospective cohort study demonstrated that total urinary resveratrol metabolite concentration was not associated with inflammatory markers, CVD, or cancer; or predictive of all-cause mortality [291], thus suggesting that there is no benefit to resveratrol supplementation in humans. However, this study investigated these outcomes in older community-dwelling adults who consume resveratrol as part of their regular diet and the amount of resveratrol consumed from the dietary sources is much lower than the therapeutic doses of resveratrol used in clinical trials. Since most of the effects of resveratrol are dosedependent [292], the negative findings from the observational study [291] is probably not representative of the effects of resveratrol when administered as a nutraceutical. That said, two other clinical studies showed that resveratrol blunted some of the protective cardiovascular effects of exercise in aged men [293, 294], further raising doubt on the effectiveness of resveratrol in humans. Therefore, it is important to address the challenges that face the translation of the very promising preclinical results to real-world clinical benefits of resveratrol. Perhaps one of the largest challenges associated with resveratrol is its low bioavailability [295-297]. Although resveratrol is highly absorbed when given orally, it has a very low bioavailability due to rapid metabolism to its glucuronide and sulfate conjugates [298]. Administration of approximately 25 mg resveratrol results in plasma concentrations that are between 1 and 5 ng/mL [299], and administration of even larger amounts, up to 5 g, still only yield 500 ng/mL (2 μM) [300]. This has resulted in the concept of the “resveratrol paradox”,

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which describes a molecule with a very low plasma concentration that has multiple biological effects [301]. To explain this, a number of theories have been proposed ranging from resveratrol concentrating in certain organs [302] to the evidence that shows the conversion of sulfated conjugates of resveratrol back to the parent compound in certain cell types [303]. Although this latter concept presents a possible explanation for the in vivo results observed for resveratrol for the treatment of CVD, it needs to be investigated whether or not cardiomyocytes (or other cardiovascular target cells) also have the ability to transport the sulfated conjugates of resveratrol into the cell to be metabolized back to the parent compound [303]. Of interest, a recent study has demonstrated the accumulation of resveratrol metabolites, resveratrol-3-sulfate and resveratrol-3-glucuronide, in heart tissues of diabetic rats in a dose and time-dependent manner [251]. The myocardial accumulation of these metabolites was associated with improvement in cardiac function [251], raising the possibility that the pharmacological effects of resveratrol are mediated, at least in part, through active metabolites.

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Due to the poor bioavailability of resveratrol, there remains a question as to what dose should be used for clinical studies? In the animal studies reviewed herein, effective doses have ranged from as low as 0.1 mg/kg/day up to 800 mg/kg/day (see Tables 1-6). Similarly, in clinical studies, doses of resveratrol range from 10 mg/kg/day to 1000 mg/kg/day (Table 7). This issue of dose is particularly important as several resveratrol effects are dose-dependent (discussed earlier). Furthermore, since resveratrol may exhibit a hormetic dose-response, this further complicates a dose selection for clinical studies [304]. Another important and related question is what method of administration should be chosen. Although resveratrol is poorly soluble in aqueous solutions [305], some preclinical studies administer resveratrol in the drinking water, which may create dose variability issues. How this hurdle will be overcome in clinical trials has yet to be addressed but the poor solubility of resveratrol may be enhanced by increasing its aqueous solubility via microparticulate systems, cyclodextrin complexes, nanocarrier systems, or even vesicular systems (reviewed in [297]). Whether or not this will improve the effectiveness of resveratrol in clinical studies has yet to be tested. Since the clinical data for the effectiveness of resveratrol are still limited, it is difficult to confirm or refute its potential beneficial effects in the treatment of humans with CVD. Although we have a few human trials, the cardiovascular effects of resveratrol have never been tested in a large double-blinded placebo-controlled clinical trial (Table 7) and the largest clinical trial has only enrolled 66 patients [75]. Moreover, most of the beneficial cardiovascular effects of resveratrol have occurred in clinical studies that had a primary focus on diabetes and/or other metabolic diseases and CVD was not their primary outcome. As such, many important cardiovascular parameters were not measured. In addition, clinical studies involving resveratrol have been limited to investigating the short-term effects of resveratrol, not its long-term cardiovascular protective outcomes. Since the development of some CVDs such as atherosclerosis and cardiac hypertrophy occur over many years [97, 306], long-term studies are warranted to examine the beneficial effect of resveratrol on the pathogenesis of these diseases. In addition to effectiveness, long-term clinical trials are needed to confirm the long-term safety of resveratrol, which is still unknown. Taking into account the multitude of molecular targets affected by resveratrol, it is very hard to predict its long-term adverse effects, and its interaction

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with specific disease states. In addition to compound safety, the potential drug-interaction with resveratrol should also be considered, since resveratrol has been shown to inhibit the phenotypic indices of the Cytochrome P450 (CYP) 3A4, CYP2D6, and induce that of CYP1A2 in human subjects taking 1 gram of resveratrol once daily for 4 weeks [307]. The effects that resveratrol has on these enzymes suggest that further studies to investigate its efficacy and safety are urgently needed.

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Adding some confusion to our understanding of the effectiveness of resveratrol in humans is the use of a mixture of polyphenolic compounds instead of pure resveratrol in some studies [137, 308-311]. These studies are also creating some confusion about whether the observed effects are mainly due to resveratrol or due to other polyphenols. Although some clinical studies have measured the resveratrol content in the grape extract, and administered a resveratrol-free grape extract as a control, there is still a possibility that other polyphenols synergize the effects of resveratrol [309]. Moreover, some meta-analyses combine the data from studies that used pure resveratrol with data collected from studies that used a polyphenolic mixture [80], which makes the final conclusion of these meta-analyses also difficult to interpret. Unfortunately, the large controlled trials needed to confirm the effects of resveratrol in the treatment of CVD have not been performed.

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In an era of personalized medicine, resveratrol should not be expected to treat all CVDs in all patient groups. Therefore, it is important to identify target CVDs and target patient groups that will respond the most to resveratrol in clinical trials. For example, it is has been proposed that the effect of resveratrol on insulin signalling is dependent on the metabolic status of the patient (i.e. insulin resistant or not) [312] and a similar dependency may be the case with the potential cardiovascular benefits of resveratrol. Indeed, the beneficial cardiovascular effects of resveratrol were mostly observed in diabetic patients [74, 75], suggesting that the cardiovascular benefits of resveratrol may be more readily apparent in this patient population where CVD is a common co-morbidity. In agreement with this notion, resveratrol treatment has been shown to significantly lower systolic BP in a recent meta-analysis of clinical trials investigating the effect of resveratrol in patients with type 2 diabetes [313]. As such, it will be important to perform clinical trials that compare the cardiovascular effects of resveratrol in diabetic patients to its effects in non-diabetic patients with identified CVDs. In conclusion, studies using resveratrol have demonstrated several convincing beneficial cardiovascular effects in preclinical studies. In some instances, these findings have provided the foundation needed for testing resveratrol in humans. Unfortunately, the clinical studies investigating the beneficial cardiovascular effects of resveratrol are still limited and there is a need for large well-controlled clinical studies to study the effect of resveratrol in patients with defined CVDs. Until that time, the benefits of resveratrol in the treatment of patients with CVDs will remain as is; holding great promise but not yet proven.

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ACCEPTED MANUSCRIPT Acknowledgements

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This work was funded by the Canadian Institutes of Health Research (CIHR) to JRBD. BNMZ and IMR are the recipients of postdoctoral fellowships from CIHR and Alberta Innovates – Health Research (AIHS).

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ACCEPTED MANUSCRIPT Table 1: The Anti-hypertensive Effects of Resveratrol in Animal Models

High fructose corn syrup

5 weeks

Reduced SBP

30 days

Rat model of 20 preeclampsia mg/kg/day, by orogastric route SHR 50 mg/l in drinking water (5 mg/kg/day) Estradiol-17β- 0.84 g/kg diet induced hypertension in female rats Two-kidney, 10 mg/kg/day one-clip IP hypertensive rat SHR 2.5 mg/kg/day by oral gavage Angiotensin II 800

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Reduced SBP

[25]

[25]

Reduced SBP, DBP, TG, and [314] LDL-cholesterol

10 weeks

Reduced SBP, TG, and total [35] cholesterol

6 weeks

No effect on BP. Improved [315] diastolic function in obese prone rats

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2 weeks

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Effect on Blood Pressure

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Angiotensin II infused mice

Resveratrol Dose 320 mg/kg/day mixed with diet 146 mg/kg/day Mixed with diet 30 mg/kg/day by oral gavage 50 mg/l in drinking water 2.5 mg/kg/day by oral gavage

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Throughout pregnancy

No effect on BP

10 weeks

Reduced SBP, DBP, and heart [26] weight/body weight ratio

41 days

Reduced SBP and DBP

6 weeks

10 weeks

Reduced BP, ameliorated [28] cardiac hypertrophy, and improved left ventricular function No effect on BP [39]

4 weeks

Reduced

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BP,

[316]

[317]

ameliorated [215]

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Reduced weight

SBP

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heart [29]

Reduced SBP, and alleviated [36] cardiac hypertrophy

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8 weeks

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8 weeks

Reduced SBP

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4 weeks

No effect on BP

[40]

4 weeks

Reduced systolic BP

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2 weeks

Reduced Systolic BP

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Reduced SBP

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3 weeks

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Obese Zucker 10 mg/kg/day rats by oral gavage High fat diet – 20 mg/kg/day female rats mixed with diet Partially 50 mg/kg/day nephrectomize by oral d rats gavage Fructose 10% 10 mg/kg/day in drinking by oral water gavage Ovariectomzie 5 mg/kg/day d female rats SHR 0.448 mg/L4.44 mg/L in drinking water DOCA-salt 1 mg/kg/day hypertensive orally rats Angiotensin II 4 g/kg diet -infused mice (320 mg/kg/day) 10% fructose- 10 mg/kg/day fed rats Pulmonary hypertension Monocrotaline- 25 mg/kg/day induced in drinking pulmonary water hypertension

cardiac hypertrophy, and partially prevented angiotensin-II induced coronary and myocardial damage Reduction in SBP. Reduction [34] in plasma levels of total cholesterol and triglycerides Reduced BP [38]

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Monocrotalineinduced pulmonary hypertension

14 or 21 days, starting one day post monocrotali ne 10 – 30 21 days, mg/kg i.g. starting twice daily after the monocrotali ne

Prevented the increase in [70] right-ventricular systolic pressure, and right-ventricular hypertrophy

Dose-dependent amelioration [69] of RV free wall thickness, RV systolic pressure, and decreased pulmonary arterial acceleration

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Reversed established [71, 72] pulmonary hypertension (attenuated RV systolic pressure, and RV hypertrophy)

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Pre-treatment with resveratrol [73] significantly reduced mean pulmonary artery pressure

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PTE-induced acute pulmonary hypertension

3 mg/kg/day 14 days, in drinking starting 28 water days post monocrotali ne 10 mg/kg IP Two doses, 1 h before the start of the PTE, and then for another 8 h

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ACCEPTED MANUSCRIPT Table 2: Effect of Resveratrol on Plasma Lipids and Atherosclerosis

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Effect

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Reduced oxidized LDL, no [96] effect on Total Cholesterol, LDL, HDL, or TG

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Reduced level of cholesterol and TG

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Resveratrol Duration Dose High fat diet- 1 mg/kg body 45 days fed male weight in Wistar rats drinking water Atherogenic 0.0125% Diet 8 weeks diet-fed C57BL6/J mice High fat diet- 0.025% Diet 8 weeks fed male Syrian Golden Hamster ApoE-deficient 0.02 and 20 weeks male mice 0.06% diet 2% high 20 mg/kg/day 2 weeks cholesterol - orally diet-fed male SpragueDawley rats

Reduced level of cholesterol and TG

plasma [87]

plasma [88]

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High cholesterol diet-fed male New Zealand rabbits High cholesterol diet-fed male New Zealand rabbits Female CD rats High cholesterol diet-fed New Zealand rabbits

3 mg/kg/day 12 weeks - orally

Reduced total cholesterol and [89] LDL Reduced plasma total [90] cholesterol, TG, LDL levels. Improved functional recovery after ex-vivo I/R injury. Increased capillary density after in vivo LAD occlusion for one week No change in lipid profile. [95] Reduced atherosclerotic plaques. Improved FMD

4 mg/kg/day 4 weeks - orally

No change in lipid profile. [318] Significant reduction in ADPinduced platelet aggregation

20 and 40 21 days mg/kg/day IP 0.6 60 days mg/kg/day for 5 days, then 1 mg/kg/day from day 6 to

No change in lipid profile

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No change in lipid profile. [320] Increased atherosclerotic lesions

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No change in lipid profile [94] Significant anti-atherosclerotic and anti-inflammatory effect Decreased LDL, VLDL, TG; [91] increased HDL; decreased markers of platelet activation

200 mg/kg 8 weeks diet/day

Decreased LDL and total [92] Cholesterol; increased HDL; no effect on TG Decreased TG, and total [321] cholesterol

mg/kg 12 weeks

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60 (dissolved in ethanol, injected IP) 2 mg/kg/day 24 days in diet

Reduced SBP, DBP, TG, and [314] LDL Reduced SBP, TG, and total [35] cholesterol

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ACCEPTED MANUSCRIPT Table 3: Effect of Resveratrol on Myocardial Ischemia and Ischemia-reperfusion Injury

Effect on Infarct Size, Cardiac Ref Function and Survival 60 min prior BP and HR unaffected, no [160] to occlusion reduction in infarct size, no reduction in arrhythmia, improved survival

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60 min prior BP and HR unaffected, [160] to occlusion reduced infarct size, reduced incidence of arrhythmia, and improved survival

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15 min prior Reduced infarction and [163] to occlusion improved cardiac function

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Resveratrol Dose Rats with left 0.5 mg/kg IP coronary artery temporary ligated and reperfused Rats with left 1 mg/kg/day coronary IP artery temporary ligated and reperfused Rats with left 10 μM IV coronary artery temporary ligated and reperfused Mice with left 5 mg/kg IP coronary artery temporary ligated and reperfused Rats with left 20 mg/kg/day by oral coronary gavage artery permanently ligated Rats with left 10 mg/kg/day by oral coronary gavage artery permanently ligated Rats with left 1 mg/kg/day (8 mg/ml in coronary drinking artery water) permanently ligated

24 hours Reduced infarct size prior to occlusion

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Reduced infarct size, [90] increased capillary density, and improved cardiac function

4 weeks

Reduced infarct size, improved [159] contractile function, and improved survival

18 days

Reduced infarct size and [161] improved cardiac function

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2.5 16 weeks mg/kg/day by oral gavage

No change in infarct size, no [165] effect on cardiac function, no improvement on cardiac remodeling, and no change in survival No decrease in infarct size, no [167] improvement in cardiac function, and no difference in survival

4 weeks

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0.1 mg/kg/day IP

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17 mg/kg/day 13 weeks in diet

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100 11 weeks mg/kg/day in diet

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oral

SC

by gavage

AC CE P

coronary artery permanently ligated Yorkshire miniswine with an ameroid constrictor Rats with left coronary artery permanently ligated Rats with left coronary artery permanently ligated Rats with left coronary artery permanently ligated Rats with left coronary artery permanently ligated Mice with left coronary artery permanently ligated Mice with left coronary artery permanently ligated Mice with left coronary artery permanently

Prevented hypertrophic [158] remodeling, reduced infarct size, reduced incidence of ventricular arrhythmias, and improved survival Improved perfusion, preserved [162] vessel formation, decreased wall motion abnormalities, and improved cardiac function Improved cardiac function and [169] survival

NU

Rats with left 5 mg/kg/day 4 weeks

1 mg/kg/day 4 weeks IP

Reduction of infarct size, [167] improved cardiac function, and no difference in survival

20 mg/kg/day 6 weeks IP

Decreased hypertrophy, [168] reduced infarct size, improved cardiac function, and improved survival

5 mg/kg/day 2 weeks by osmotic pump

No change in cardiac [171] hypertrophy, infarct size, or cardiac function

50 mg/kg/day 2 weeks by osmotic pump

Reversed cardiac hypertrophy, [171] reduced infarct size, and improved cardiac function

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PT

Dose-dependent reduction in [284] the duration of arrhythmia, arrhythmia score, incidence of VT, and mortality

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ligated Rats with left 5, 15, 45 10 minutes mg/kg IV prior to coronary occlusion artery permanently ligated

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ACCEPTED MANUSCRIPT Table 4: Effect of Resveratrol on Cardiac Hypertrophy/function

8 weeks

PT

Ref [30]

[32]

[31]

[208]

D

MA

2 weeks

RI

10 weeks

SC

2 weeks

Effect on Cardiac Hypertrophy/Function No effect on BP, reduced cardiac hypertrophy, and improved cardiac function. No effect on BP, reduced cardiac hypertrophy, and improved cardiac function Alleviated cardiac fibrosis. No effect on BP, diastolic function, or vascular remodeling Reduced cardiac hypertrophy, and improved cardiac function

NU

Duration

26 days

No effect hypertrophy dysfunction

on and

cardiac [210] cardiac

14 days

No effect hypertrophy, dysfunction

on and

cardiac [210] cardiac

26 days

Reduced cardiac hypertrophy, [210] and improved cardiac function

14 days

Reduced cardiac hypertrophy, [210] and improved cardiac function

4 weeks

Reduced SBP and cardiac [29] hypertrophy

45 days

Reduced SBP and cardiac [36]

TE

Resveratrol Dose SHR 2.5 mg/kg/day by oral gavage SHR 2.5 mg/kg/day by oral gavage SHR 2.5 mg/kg/day by oral gavage Rats with 2.5 abdominal mg/kg/day by aortic banding- oral gavage induced pressureoverload Rats with 2.5 shunt induced mg/kg/day by volumeoral gavage overload Rats with 2.5 shunt induced mg/kg/day by volumeoral gavage overload Rats with 2.5 abdominal mg/kg/day by aortic banding- oral gavage induced pressureoverload Rats with 2.5 abdominal mg/kg/day by aortic banding- oral gavage induced pressureoverload Partially 50 mg/kg/day nephrectomize by oral d rats gavage Fructose 10% 10 mg/kg/day

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Animal model

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ACCEPTED MANUSCRIPT hypertrophy

PT

No effect on BP, improved [315] cardiac function

RI

Reduced cardiac hypertrophy, [209] reduced remodeling, and improved cardiac function

SC

Reduced cardiac hypertrophy, [212] improved cardiac function, and improved survival

NU

by oral gavage 2.5 6 weeks mg/kg/day by oral gavage Mice with 10 mg/kg/day 4 weeks TAC-induced by oral pressuregavage overload TO-2 145 29 weeks Hamsters mg/kg/day in prone to Heart diet Failure Experimental 50 mg/kg/day 2-3 weeks model of IP Autoimmune Myocarditis in rats Dahl-salt 18 mg/kg/day 8 weeks sensitive rats in diet

Reduced cardiac hypertrophy, [211] reduced remodeling, and improved cardiac function

No effect on BP, reduced [217] hypertrophy, improved cardiac function and improved survival

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in drinking water Rats fed High fat diet

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ACCEPTED MANUSCRIPT Table 5: Effects of Resveratrol in Chemotherapy-induced Cardiotoxicity

Effect

Acute Doxorubicininduced cardiotoxicity in rats Acute doxorubicininduced cardiotoxicity in rats Sub-acute

Ref

5 weeks, starting one week before DOX injection

Alleviated DOX-induced [289] cardiac damage (decreased CK and LDH activity), decreased DOX-induced cardiomyocyte apoptosis

4 g/kg diet

8 weeks

Improved LV function, [262] improved exercise capacity

MA

NU

SC

RI

PT

Duration

D

20 mg/kg/day 4 weeks, Alleviate DOX-induced [261] by oral starting 2 oxidative stress, inflammation, gavage weeks apoptosis, and fibrosis. before DOX 10 mg/kg/day 7 weeks, Alleviated DOX-induced [263] IP starting 2 cardiac dysfunction. weeks before DOX

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Chronic Doxorubicininduced cardiotoxicity in Balb/c nude mice Chronic Doxorubicininduced cardiac dysfunction in C57BL/6 mice Chronic Doxorubicininduced cardiotoxicity in rats Chronic Doxorubicininduced cardiotoxicity in rats Sub-acute Doxorubicincardiotoxicity in rats

Resveratrol Dose 10 mg/kg/day by oral gavage

TE

Model

5 mg/kg 5 days every other day 1 h before and 2 h after DOX injection 30 and 120 3 days mg/kg/day IP

Alleviated bradycardia prolongation.

15 mg/kg IP

Alleviated DOX-induced [265] histological damage.

5,

15,

Alleviated DOX-induced [264] oxidative stress and histological damage.

Single dose

45 10

DOX-induced [266] and QTc

days, Alleviated

41

cisplatin-induced [270]

ACCEPTED MANUSCRIPT mg/kg/day by starting 5 myocardial damage in a doseoral gavage days before dependent manner cisplatin

SC

RI

PT

Alleviated arsenic trioxide- [277] induced QTc prolongation, myocardial damage

NU

Improved arsenic trioxide- [276] induced myocardial damage

MA

3 mg/kg IV 3 doses, every other one hour day before arsenic trioxide administrati on 8 mg/kg IV 4 doses, every other one hour day before arsenic trioxide

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cisplatininduced cardiotoxicity in rats Sub-acute arsenic trioxideinduced cardiotoxicity in BALB/C mice Sub-acute arsenic trioxideinduced cardiotoxicity in rats

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ACCEPTED MANUSCRIPT Table 6: Effects of Resveratrol in Diabetic Cardiomyopathy Resveratrol Duration Dose Models of type 1 diabetes Streptozocin2.5 15 days induced mg/kg/day – diabetic rats orally

Effect

Ref

PT

Model

[246]

[247]

[242]

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D

MA

NU

SC

RI

Reduction of blood glucose. Improvement of LV function. Reduction of the infarction size when subjected to ischemic injury. 2.5 2 weeks Enhancement of GLUT-4 mg/kg/day – translocation and glucose orally uptake in the diabetic myocardium. 1 mg/kg/day 30 days Enhancement of glucose – orally utilization. Normalize free fatty acid oxidation. Reduction of biomarkers of oxidative stress in the diabetic myocardium. 2.5 8 weeks Improved cardiac function. mg/kg/day – Decreased unfavorable IP cardiac remodeling. Reduced inflammatory state. 1 mg/kg/day 1, 3, or 6 Improved cardiac function. or 5 weeks Dose-dependent recovery of mg/kg/day – all hemodynamic parameters IP after 6 weeks. StreptozocinAbout 100 12 weeks No effect on blood glucose induced mg/kg/day – noted on the 12 weeks. diabetic mice mixed with Increase survival. Improve diet cardiac function. Decrease interstitial fibrosis. Low dose - 16 weeks Improved cardiac function. about 60 Ameliorated oxidative injury. mg/kg/day, Reduced apoptosis. No High dose – significant difference between about 300 the low dose and the high mg/kg/day – dose. mixed with diet Models of type 2 diabetes Leprdb diabetic 20 mg/kg/day 4 weeks Ameliorated diastolic mice – orally dysfunction. Decreased oxidative/nitrative stress.

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[249]

[251]

[233]

[250]

[252]

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200 6 weeks mg/kg/day – mixed with diet

Improved LV developed [254] pressure and coronary flow in diabetic hearts. Reduced fibrosis, [257] mitochondrial dysfunction, reactive lipid accumulation, and mitochondrial ROS.

PT

5 mg/kg/day 4 months – orally

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TE

D

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SC

RI

Streptozocinnicotinamide model in rats Zucker Diabetic Fatty (ZDF) rat

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ACCEPTED MANUSCRIPT Table 7: Cardiovascular Effects of Resveratrol in Clinical Studies

Cardiovascular Effect

Ref

45 days

Reduction of SBP and [75] LDL, increase in HDL, No change in total TG and total Cholesterol.

250 mg/day

90 days

150 mg/day

30 days

Reduction of SBP, [76] plasma TG levels.

90 days

Improved FMD. No [79] effect on BP or lipid profile.

90 days

No effect pressure.

75 mg/day

42 days

Improved FMD. No [82] effect on blood pressure.

500 mg/day

28 days

No effect on blood [139] pressure. No effect on lipid profile.

1 – 2 g/day

28 days

No change in BP or [322] plasma lipids. A trend toward improved post-

MA

NU

SC

RI

PT

Duration

100 mg/day

AC CE P

Randomized placebocontrolled doubleblinded parallel Patients with Prospective, Type 2 open-label, Diabetes randomized (n=62) Healthy Randomized, obese men placebo(n=11) controlled double-blind crossover Patients with Open-label, metabolic randomized syndrome (n=34) Overweight Double-blind, older adults randomized, (n=32) placebocontrolled trial Healthy Randomized, obese adults placebo(n=28) controlled double-blind crossover Healthy Randomized, obese men placebo(n=24) controlled, doubleblinded, and parallelgroup Older Open-label subjects with impaired

Resveratrol dose 1 gram/day

D

Study design

TE

Study population Patients with Type 2 Diabetes (n=66)

300 mg/day

Reduction of SBP, total [74] cholesterol, LDL, and HbA1c

on

blood [290]

1000 mg/day

45

ACCEPTED MANUSCRIPT glucose tolerance (n=10) Postinfarction Caucasian patients with stable CAD (n=40) Patients with stable angina pectoris

meal reactive hyperemia index. 10 mg/day

90 days

Reduced LDL, [199] improved FMD and LV diastolic function. A trend toward improved LV systolic function.

Randomized, doubleblinded, activecontrolled, parallel OverDouble-blind, weight/obese placebomen or controlled, postmenopa randomized usal women crossover with borderline hypertension (n=19) Non-obese, Randomized, postdouble-blind, menopausal placebowomen controlled (n=45) Healthy adult Randomized, smokers double-blind, (n=50) placebocontrolled, crossover Overweight/o Randomized, bese men double-blind, with mild placebohypertriglyce controlled, ridemia (n=8) crossover

20 mg/day

60 days

Significant reduction of [194] CRP and NT-proBNP. Slight improvements in lipid profile from baseline. Improvement in quality of life. Improved FMD one [323] hour after resveratrol ingestion in a dosedependent manner.

Randomized, double-blind, placebocontrolled,

SC

NU

TE

D

MA

30, 90, 270 Single mg ingestion

AC CE P

Healthy adults (n=22) Randomized, double-blind,

RI

PT

Double-blind, placebocontrolled

75 mg/day

84 days

No effect on blood [78] pressure or plasma lipids.

500 mg/day

30 days

Significant reduction in [136] triglyceride concentration. No effect on blood pressure.

1 g/day for 14 days the first week, 2 g/day for the second week 250 or 500 Single mg dose

No effect on plasma TG [138] or cholesterol levels. Reduction in intestinal and hepatic lipoprotein particles production.

46

Dose-dependent [153] increase in cerebral blood flow during task performance – pattern

ACCEPTED MANUSCRIPT crossover

suggests the involvement of NO. Increase cerebral blood [152] flow.

PT

Single dose

TE

D

MA

NU

SC

RI

Randomized, double-blind, placebocontrolled, within-subject

AC CE P

placebocontrolled, crossover Healthy adults (n=23)

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ACCEPTED MANUSCRIPT

Figure 1. Proposed mechanisms of the anti-hypertensive effect of resveratrol. The antihypertensive effect of resveratrol is mediated through activation of AMP-activated protein kinase (AMPK), silent information regulator 1 (SIRT1), and nuclear factor erythroid-2 related factor 2 (NRF2), which lead to both endothelium-dependent and endothelium-independent vasorelaxation. Multiple cross talks exist among these pathways.

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Figure 2. Proposed anti-ischemic mechanisms of resveratrol. Resveratrol confers its antiischemic effects through activation of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), and inhibition of reactive oxygen species (ROS) and atherosclerosis.

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Figure 3. Proposed mechanisms of the protective effects of resveratrol against cardiac hypertrophy and heart failure. Resveratrol interferes with several processes implicated in the pathophysiology of cardiac hypertrophy and heart failure. Resveratrol activates AMP-activated protein kinase (AMPK) through the LKB1 pathway leading to inhibition of both protein synthesis and nuclear factor of activated T cells (NFAT)-mediated hypertrophic gene expression. Resveratrol also induces autophagy through both AMPK and silent information regulator 1 (SIRT1) pathways. Lastly, resveratrol inhibits reactive oxygen species (ROS) generation by activating the anti-oxidant enzyme superoxide dismutase (SOD).

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ACCEPTED MANUSCRIPT REFERENCES:

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Resveratrol has beneficial effects in animal models of cardiovascular diseases. Several molecular mechanisms contribute to the beneficial effects of resveratrol. Clinical studies of resveratrol are still limited. The benefits of resveratrol are holding promise but are not yet proven.

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