Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy

diabetes research and clinical practice 100 (2013) 330–339

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Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es

Review

Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy T.-I. Lee a,b, Y.-H. Kao c,d,**, Y.-C. Chen e, J.-H. Huang f, F.-C. Hsiao d,g, Y.-J. Chen d,f,* a

Department of General Medicine, College of Medicine, Taipei Medical University, Taiwan Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan c Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taiwan d Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taiwan e Department of Biomedical Engineering, National Defense Medical Center, Taiwan f Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan g Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taiwan b

article info

abstract

Article history:

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among

Received 15 August 2012

patients with diabetes mellitus (DM). Chronic inflammation and derangement of myocardial

Received in revised form

energy and lipid homeostasis are common features of DM. The transcription factors of

23 October 2012

peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor super-

Accepted 3 January 2013

family, which are important in regulating energy and lipid homeostasis. There are three

Published on line 28 January 2013

PPAR isoforms, a, g, and d, and their roles have been increasingly recognized to be important in CVD. These three isoforms are expressed in the heart and play pivotal roles in myocardial

Keywords:

lipid metabolism, as well as glucose and energy homeostasis, and contribute to extra

Peroxisome proliferator-activated

metabolic roles with effects on inflammation and oxidative stress. Moreover, regulation

receptors

of PPARs may have significant effects on cardiac electrical activity and arrhythmogenesis.

Cardiomyocytes

This review describes the roles of PPARs and their agonists in DM cardiomyopathy,

Diabetes mellitus

inflammation, and cardiac electrophysiology. # 2013 Elsevier Ireland Ltd. All rights reserved.

Hypertension

Contents 1. 2. 3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myocardial PPAR expressions during lipid and energy disequilibrium. Cardiac PPARs in DM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. PPAR-a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. PPAR-g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. PPAR-d . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Myocardial PPARs in hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. PPAR-a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Graduate Institute of Clinical Medicine, Taipei Medical University, Taiwan. Tel.: +886 2 27390500; fax: +886 2 29339378. ** Corresponding author. E-mail addresses: [email protected] (Y.-H. Kao), [email protected] (Y.-J. Chen). 0168-8227/$ – see front matter # 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.diabres.2013.01.008

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331 331 332 332 332 333 333 333

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diabetes research and clinical practice 100 (2013) 330–339

5.

6. 7.

1.

4.2. PPAR-g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. PPAR-d . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PPARs modulate myocardial inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. PPAR-a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. PPAR-g . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. PPAR-d . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of PPAR-g ligands in cardiac electrophysiology and Ca2+ handling in DM and hypertension Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide [1], and is frequently characterized by fatty acid (FA) dysregulation. In people with diabetes mellitus (DM) CVD morbidity and mortality is increased compared with the general population [2,3]. Additionally, hypertension is a common comorbidity in DM, and plays an important role in determining prognosis [4]. A normal heart consumes more energy than any other organ in the body and depends primarily on the catabolism of FA, which provides the large amount of energy required to support normal cardiac function [5]. Disturbances in myocardial energy and lipid homeostasis are common features of DM [6], and one of the important determinants in the homeostasis of myocardial energy and lipid metabolism is the network of transcription factors that direct the energy substrates of various metabolic pathways through expression of key proteins [5]. Peroxisome proliferator-activated receptors (PPARs) are important nuclear hormone receptors and are named for their ability to produce hepatic peroxisome proliferation in response to xenobiotic stimuli [7]. PPARs are represented by a group of three receptors PPAR-a, PPAR-g, and PPAR-d [7], which are encoded by separate genes and differ in their distribution, function, and ligand specificity. PPARs act as ligands and heterodimerize with the retinoid X receptor in the promoter region of target genes controlling every step during the uptake, utilization, oxidation, and storage pathways of FA [8]. These coordinated effects in the control of metabolism may also help regulate inflammation and atherosclerosis in the cardiovascular system [9]. Natural ligands were identified and synthetic ligands have been developed selectively for each PPAR isoform. In this review, we describe the roles of PPARs and their agonists during pathologic conditions in the heart of people with diabetes.

2. Myocardial PPAR expressions during lipid and energy disequilibrium In the physiological states, FAs and carbohydrates serve as substrates for energy metabolism in mammalian cardiomyocytes [10]. Free FA (FFA) metabolism is preferred during unstressed conditions due to the higher amount of energy that can be metabolized [11]. However, in stressed conditions such as myocardial hypertrophy or heart failure, cardiomyocytes revert back to utilizing glucose due to compromised oxygen supply. To maintain optimal cardiac function, there should be

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334 334 334 334 334 335 335 336 337 337

a balance between energy production and expenditure and between FA and glucose metabolism. Abnormal energy metabolism either by excessive accumulation of lipids or a shortage of energy can lead to a range of cardiac diseases. PPARs play important roles in regulating lipid energy metabolism and its homeostasis, and the three PPAR subtypes are expressed in the cardiomyocytes. PPAR-a is expressed in relatively abundant levels in the heart and regulates cardiac metabolism by controlling expression of enzymes directly involved in FA oxidation. It has an anti-inflammatory action and keeps oxidant and antioxidant defenses in equilibrium. The functional and biological roles of PPAR-a include regulation of mitochondrial FA oxidation, and lipoprotein assembly and transport [12]. A decrease in PPAR-a expression is a sort of adaptation by shifting the substrate utilization of cardiac energy from FA to glucose. Glucose-mediated inhibition of FFA metabolism is a key to the adjustment to various pathologic stresses such as hypertrophy and ischemia, that is partly achieved by downregulation of PPAR-a [13]. On the other hand, PPAR-g is mainly expressed by adipose tissues and is least expressed in the heart [14]. PPAR-g regulates glucose metabolism and lipogenesis and has been demonstrated to have anti-inflammatory, antihypertrophic, and antiatherosclerotic effects [15]. Under certain pathological conditions, cardiomyocytes can express a relatively large amount of PPAR-g that can have significant effects on the heart’s metabolic homeostasis and function. However, the exact mechanism of how PPAR-g regulates heart metabolism remains unclear. PPAR-g has been reported to demonstrate multiple effects on the vascular system, which are protective against hypertension, atherosclerosis [16], and ischemic reperfusion injury [17]. Nonetheless, PPAR-g agonists (thiazolinediones) were also associated with adverse effects on body weight gain and fluid retention resulting in an increased incidence of congestive heart failure, especially when combined with insulin therapy [18]. Additionally, there has been controversy regarding an increase in cardiovascular events including myocardial infarction and congestive heart failure in humans with the use of the PPAR-g agonist, rosiglitazone [19–21]. The U.S. Food and Drug Administration has restricted rosiglitazone prescription within the confines of Risk Evaluation and Mitigation Strategy, and the European Medicines Agency suspended the market authorization of rosiglitazone due to the concern about cardiovascular safety [22]. PPAR-d is ubiquitously expressed in many tissues [7]. The basic function of PPAR-d appears to be related to transcriptional programs which enhance FA metabolism, and the

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diabetes research and clinical practice 100 (2013) 330–339

uncoupling of energy in a similar manner as PPAR-a. PPAR-d is therefore critical to FA oxidation regulation where FAs act as the main source of energy [23]. This can be demonstrated by shutting off cardiac-specific expression of PPAR-d resulting in the downregulation of the genes for FA oxidation and causing an increase in glucose oxidation which is usually seen in patients with myocardial hypertrophy and congestive heart failure [23]. However, only a few studies have addressed the role of PPAR-d in CVD.

3.

Cardiac PPARs in DM

The cardiac phenotype of DM is characterized by increased FFA uptake and oxidation, with insulin resistance in the cardiomyocytes [24] which contributes to a decreased ability to switch from FFA to glucose metabolism [25]. Increased reliance on FFA metabolism thereby diminishes cardiac efficiency by increasing myocardial oxygen consumption [25] resulting in the development of cardiac lipotoxicity [26]. This impaired flexibility of FA and glucose metabolism is a key feature of myocardial cellular dysfunction in DM.

3.1.

PPAR-a

It has been shown that transgenic animal models with PPAR-a overexpression develop cardiomyopathy mimicking the DM condition [27]. However, cardiomyopathy was prevented by restricting dietary fat in these overexpressed PPAR-a animals. This implies that serum FFA is an essential mediator during cardiac maladaptation [26]. Paradoxically, although chronic exposure to FA excess downregulates PPAR-a expression in the cardiomyocytes, the downregulation of PPAR-a may result

in further myocardial damage by suppressing cellular FFA oxidation on a background of excess FFAs within cells and in the circulation [28]. Moreover, DM patients are also at higher risk for hypertension and left ventricular (LV) hypertrophy (LVH). Metabolic changes associated with LVH contribute to the progression to DM cardiomyopathy and consequent morbidity and mortality [11]. As shown in Table 1, PPAR-a ligand, BM 17.0744 (Roche Pharmaceuticals), given orally to type 2 DM db/db mice for 8 weeks normalized cardiac metabolism but was unable to improve cardiac function [29]. Apoptosis plays a role in the pathophysiology of DM cardiomyopathy, and the PPAR-a ligand, fenofibrate was shown to suppress apoptosis [30]. This finding supports the potential role of PPAR-a ligands in DM cardiomyopathy.

3.2.

PPAR-g

In DM rat models, decreased myocardial expression of PPAR-a was accompanied by an overexpression of PPAR-g [31–33]. In contrast to PPAR-a, PPAR-g leads to a rise in lipogenic enzymes that cause an increase in the production of intracellular triglycerides [31]. In addition, recent evidence from an animal model showed that PPAR-g activation within the cardiomyocytes is associated with compromised cardiac function through its lipogenic effect [34]. This may contribute to the accumulation of intracellular triglycerides causing cardiac lipotoxicity. As shown in Table 1, the PPAR-g ligand-rosiglitazone, may also have a protective role against apoptosis in DM cardiomyopathy similar to the PPAR-a ligand [30]. Rosiglitazone was also demonstrated to decrease cardiac fibrosis and improve LV diastolic dysfunction through the inhibition of receptors for

Table 1 – Effects of peroxisome proliferator activated receptors (PPARs) ligands on diabetes mellitus (DM). PPARs isoform

Drug/dose/route

Major cardiac findings

Ref.

PPAR-a

Male DM db/db mice 4–5 weeks old

Study model

BM17.0744 at 37.9  2.5 mg/kg/day for 8 weeks, per orem (p.o.)

[25]

PPAR-a, PPAR-g

Male albino DM rats

Rosiglitazone or fenofibrate for 12 weeks

PPAR-g

Male OLETF and LETO rats at 20 weeks

Rosiglitazone at 20 mg/ kg/day for 20 weeks, p.o.

PPAR-g

OLETF and LETO rats at 30 weeks

Pioglitazone at 10 mg/ kg/day for 1 month, p.o.

PPAR-g

319 DM patients with acute myocardial infarction (MI)

Pioglitazone at 30 mg/ day, p.o.

Normalized cardiac metabolism by reducing fatty acid (FA) oxidation and increasing glycolysis and glucose oxidation in treated DM mice. Did not improve cardiac functions. Apoptosis plays a key role in DM cardiomyopathy, and both PPAR ligands decreased the left ventricular (LV)/body weight ratio, and cardiac caspase-3, tumor necrosis factor (TNF)-a, hydroxyproline, free FA, and triglycerides. Improved oxidative stress parameters, LV papillary muscle developed tension. Suppressed myocardial fibrosis with reduced receptor for advanced glycation end products, connective tissue growth factor mRNA, and protein expressions; improved LV diastolic function in DM myocardium. Effects of ischemic preconditioning (IP) on reperfusion arrhythmias deteriorated in type 2 DM rats; improved the deterioration of IP against reperfusion arrhythmias in type 2 DM rats. Pretreatment with a PPAR-g agonist produced better myocardial perfusion with reduction of reperfusion injury in diabetic patients with acute MI.

Ref., reference; OLETF, Otsuka Long-Evans Tokushima Fatty; LETO, Long-Evans Tokushima Otsuka.

[26]

[31]

[32]

[33]

diabetes research and clinical practice 100 (2013) 330–339

advanced glycated end products and connective tissue growth factor in DM myocardium [35]. Moreover, pioglitazone was observed to improve the deterioration of ischemic preconditioning against reperfusion arrhythmias in type 2 DM rats [36]. In addition, pioglitazone pretreatment in DM patients with acute myocardial infarction also resulted in better myocardial perfusion and less reperfusion injury [37].

3.3.

PPAR-d

A decrease in cardiac expression of PPAR-d was found in rats with DM cardiomyopathy [32,38]. The reduction in PPAR-d expression during hyperglycemia was associated with an increase in reactive oxygen species (ROS) production [38], tumor necrosis factor (TNF)-a, interleukin (IL)-6, and nicotinamide-adenine dinucleotide phosphate (NADPH) activities [32]. Further investigations are needed to evaluate the precise role of PPAR-d ligands in regulating DM cardiomyocytes.

4.

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Myocardial PPARs in hypertension

Hypertension is an important cause of cardiovascular morbidity and mortality in DM patients [4]. Moreover, hypertension and DM frequently coexist and lead to cardiac structural or functional dysfunction which can accelerate the progression to morbidity and mortality [39]. The beneficial effect of lowering blood pressure (BP) by PPAR activators ameliorates endothelial dysfunction through antioxidant, anti-inflammatory, antiproliferative, antihypertrophic, and antifibrotic effects [40].

4.1.

PPAR-a

As shown in Table 2, PPAR-a activation with fenofibrate suppresses the hypertension-induced increase in adhesion molecule expression such as in vascular cell adhesion molecule 1, intracellular adhesion molecule 1, cytokines,

Table 2 – Effect of peroxisome proliferator activated receptors (PPARs) ligands on hypertension. PPARs isoform

Study model

Drug/dose/route

Major cardiac findings

Ref.

PPAR-a

Male DS rats on a high-salt diet (HSD)

Fenofibrate at 30 mg/kg/day or 50 mg/kg/day at 7–18 weeks of age, per orem (p.o.)

[37]

PPAR-a

Male SD, Harlan SD, PPAR-a KO mice

PPAR-a

Cultured bovine aorta endothelial cells

Bezafibrate at 30 mg/kg/day, for 7 days, intraperitoneal (i.p.) Clofibrate at 250 mg/kg/day for 3 weeks, i.p. Bezafibrate concentrationdependent fashion (50–200 mM)

PPAR-g

Male Zucker fatty rats ( fa/fa)

YM440 at 100 mg/kg/day for 16 weeks, p.o.

PPAR-g

Obese fa/fa Zucker rats

Pioglitazone at 20 mg/kg/day for 4 weeks, p.o.

PPAR-g

Male SD rats

Rosiglitazone at 10 mg/kg/day in the last 2 weeks, p.o.

PPAR-g

Male Zucker rats

PPAR-g

Double TG (R+A+), non-TG mice (R A )

Rosiglitazone (BRL-49653) at 7– 7.5 mmol/kg/day at age 6 weeks for 3 months, p.o. Rosiglitazone at 25 mg/kg/day for 21 days, p.o.

PPAR-g

Male SHR, SHR DM

Rosiglitazone at 5 mg/kg/day for 2 weeks, p.o.

PPAR-g, PPAR-a

SHR, WKY

PPAR-d

LDLR

Rosiglitazone at 150 mg/kg/day Wy 14,643 at 50 mg/kg/day for 8 weeks, p.o. GW0742 at 1 or 10 mg/kg/day for 4 weeks, p.o.

Reduced cardiac inflammation, inhibited DNAbinding activities and the expressions of several redox-regulated transcription factors in the left ventricle (LV). Exerted protective actions against hypertension via nitric oxide (NO) production and or inhibition of endothelin (ET)-1 and nicotinamide adenine dinucleotide phosphate oxidase activity. Exerted benefits on endothelial function through increase endothelial NO synthase (eNOS) expression levels, and enhanced phosphorylation of eNOS ser1179 providing benefits as an antiatherosclerotic and antihypertensive agent. Reduced systolic blood pressure (BP) partly due to inhibition of renin–angiotensin system activation via a PPAR-g signaling pathway. Lowered BP and heart rate in obese rats fed a HSD due to antagonistic effect to angiotensin II and effects on the sympathetic nervous system. Improved metabolic profile in fructose-fed rats, reduced BP, insulin, triglycerides, oral glucose tolerance, and increased adiponectin levels. Prevented hypertension in fatty Zucker rat partly due to restoration of tonic vasorelaxant action of insulin in resistant arteries. Direct effect in blood vessels may have contributed to improved BP and vessel function. PPAR-gindependent effects on vascular tone may have potentially contributed to improved BP. Lowered mean systolic BP and diastolic BP in DM SHRs contributed to decreased inflammation and reactive oxygen species. Chronic treatment with PPAR-g agonist delayed progression to hypertension but was associated with a prohypertrophic effect. Atheroprotective effects by inhibiting angiotensin II signaling without BP alteration or suppression of inflammation.

/

mice

[38]

[39]

[41]

[42]

[43]

[44]

[45]

[29]

[48]

[50]

Ref., reference; DS, Dahl salt-sensitive; SD, Sprague–Dawley; KO, knock-out; TG, transgenic; SHR, spontaneous hypertensive rat; WKY, WistarKyoto; LDLR, low-density lipoprotein receptor.

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diabetes research and clinical practice 100 (2013) 330–339

and osteopontin [41]. Clofibrate increases nitric oxide (NO) production, inhibits endothelin (ET)-1 output, and impedes NAD(P)H oxidase activity, all of which can contribute to BP control [42]. Moreover, bezafibrate increases the endothelial NO synthase (eNOS) expression levels, and augments the phosphorylation of eNOS ser-1179 and leads to increment in NO production and transcription levels and stability of eNOS messenger mRNA through a PPAR-adependent pathway. These mechanisms provide benefits of PPAR-a ligands as anti-atherosclerotic and anti-hypertensive agents [43]. More studies are needed not only to clarify the BP effect of PPAR-a agonists, but also to fully examine the mechanisms by which PPAR-a and its ligands act in the presence of hypertension.

4.2.

PPAR-g

In heart model of spontaneously hypertensive rat (SHR), increased expression of PPAR-g was found [33], which may have been due to the accumulation of lipid uptake [34] or due to a compensatory response to cardiac hypertrophy and failure [44], thereby compromising cardiac function. Table 2 shows that in obese Zucker fatty rats, the PPAR-g ligand, YM440, resolved the rise in systolic BP compared with controls [45]. In obese rats, pioglitazone also had a blunting effect on the BP in response to angiotensin II [46]. The administration of rosiglitazone reversed the BP elevation found in a high-fructose rat model [47], and prevented the development of hypertension in Zucker rats [48]. Furthermore, the direct effect of rosiglitazone in blood vessels may contribute to the improved BP and vessel function in hypertensive transgenic mice [49]. As also shown in Table 2, the effect of lowering BP with rosiglitazone treatment in DM hypertensive rodent model contributes to a decreased inflammation and ROS of the cardiomyocytes [33]. Moreover, the common Pro12Ala polymorphism in PPAR-g was found to be clinically related with the lowering of BP in males with type 2 DM [50], and lower carotid artery intima-media thickness [51]. The effect of lowering BP with PPAR-g agonists may be due to their direct impact on the blood vessels. While activation of PPAR-g is associated with a beneficial effect on BP, it was also found to be associated with prohypertrophy [52], thus the precise roles of PPAR-g remain uncertain.

4.3.

PPAR-d

Although PPAR-d is less studied in hypertensive and DM models, reduction in the expression of PPAR-d was observed in hypertensive and DM hypertensive rats secondary to inflammation and oxidative stress [33]. Unlike PPAR-g and PPAR-a agonists, PPAR-d agonists have not been shown to have similar effects on BP regulation. In an angiotensin II infusion mouse model, a PPAR-d agonist as shown in Table 2 did not change the BP level, but was found to have an atheroprotective effect. Despite the discovery of specific PPAR-d ligands such as L1655041 [53] and GW0742X [54], the role of PPAR-d in the regulation of hypertension remains unknown.

5.

PPARs modulate myocardial inflammation

During the development of DM, several biochemical and mechanical factors cause endothelial dysfunction and vascular inflammation [55]. PPARs are expressed in the heart and have anti-inflammatory activity [56]. PPAR ligands inhibit inflammation by regulating the activities of the transcription factors, activator protein 1 and nuclear factor kappa-lightchain-enhancer of activated B cells (NF-kB) [56]. Investigations on PPAR agonists have shown that they decrease inflammatory markers such as C-reactive protein, TNF-a, and IL-1b in atherosclerotic lesions [57,58], and have cardioprotective effects against ischemia/reperfusion [59]. However, PPAR-g ligands as therapeutic agents in CVD received widespread attention due to their potential adverse effects, which were reported to increase the risk of death, cardiovascular events, and myocardial infarction [60].

5.1.

PPAR-a

The expression of PPAR-a in the cardiovascular system plays a role in controlling inflammation [61]. It was reported that PPAR-a has anti-inflammatory and antioxidative effects [62], and activation of inflammatory signaling pathways is important in cardiomyocyte hypertrophy. PPAR-a agonists, as shown in Table 3, have been used to repress inflammation caused by CVD. Pretreatment of neonatal cardiomyocytes with PPAR-a agonist significantly decreases lipopolysaccharide (LPS)-stimulated TNF-a release [15]. PPAR-a agonists also inhibit IL-1-induced secretion of IL6, and prostaglandin and cyclooxygenase-2 expressions [63]. Translocation of NF-kB to nuclei and apoptosis were also demonstrated to be reduced after treatment with the PPAR-a agonists in the reperfused myocardium [64,65]. These findings suggest an important role of PPAR-a agonists in the inhibition of inflammation in many cell types of CVD, and further support the potential role of PPAR-a agonists in suppressing inflammation associated with DM.

5.2.

PPAR-g

Although PPAR-g levels are relatively low in myocardial cells, activation of PPAR-g during inflammation might have important effects on cardiomyocytes as can be seen in Table 3. The therapeutic effects of PPAR-g ligands have been attributed primarily to their anti-inflammatory properties. Previous studies showed that both natural and synthetic PPAR-g ligands have anti-inflammatory potentials [66]. As shown in Table 3, pretreatment of neonatal cardiomyocytes with PPAR-g agonists significantly decreased LPSstimulated TNF-a release by cardiac myocytes [15]. In an autoimmune myocarditis model, PPAR-g ligands suppressed myocardial mRNA expressions of inflammatory cytokines and IL-1b [67]. Furthermore, treatment with rosiglitazone or pioglitazone decreases not only the expressions of proinflammatory markers, such as intracellular adhesion molecule1 and monocyte chemotactic protein-1 (MCP-1), but also the accumulation of neutrophils and macrophages in the reperfused myocardium [17,68]. In DM hypertensive rodents,

diabetes research and clinical practice 100 (2013) 330–339

335

Table 3 – Effect of peroxisome proliferator activated receptors (PPARs) ligands on inflammation. PPAR isoform

Study model

Dose/duration/route

PPAR-a

Hyperlipidemic patients with or without coronary artery disease

Fenofibrate at 250 mg/ day for 4 weeks, per orem (p.o.)

PPAR-a

Male New Zealand white rabbits

WY14643 at 1 mg/kg, intravenously (i.v.)

PPAR-a

Male CD1 mice PPAR-a mice PPAR-a+/+ mice

PPAR-a, PPAR-g

Primary cultures: 1-day old Wistar rats

PPAR-g

Acute EAM induced in 6week-old Lewis rats

PPAR-g

Male Lewis rats LAD occlusion

PPAR-g

Male Wistar rat

PPAR-g

SHR, DM SHR 12 weeks old

PPAR-d

5-week old CD-1 male mice Human cardiac AC16 cells

/

GW7647 at 3 mg/kg, p.o. for 2 days, 3rd dose 1 h before ischemia PPAR-a activator: Wy14643 at 100 mmol/L and gemfibrozil at 100 mmol/L PPAR-g activator: BRL49653 at 10 mmol/L and troglitazone at 10 mmol/L 15d-PGJ2 at 200 mg/kg/ day, intraperitoneal (i.p.), pioglitazone at 10 mg/kg/day, p.o for 3 weeks Rosiglitazone at 1 and 3 mg/kg, i.v., 1/2 dose before and after MI/R injury Pioglitazone at 3 mg/kg/ day, p.o. 7 days before and after MI/R injury Rosiglitazone at 5 mg/ kg/day for 2 weeks, p.o.

GW501516 at 3 mg/kg/ day, p.o. for 3 weeks

Major cardiac findings

Ref.

Inhibited interleukin (IL)-6, prostaglandin, and cyclooxygenase-2 expressions by aortic smooth-muscle cells with beneficial effects on vessels in atherosclerosis and postangioplasty restenosis. Diminished the occurrence of apoptosis, lessened myocardial injury which may have been related to nuclear factor (NF)-kB translocation, and reduced the NF-kBmediated inflammation response. Reduced myocardial ischemia/reperfusion (MI/R) injury, improved contractile function mediated by metabolic and antiinflammatory mechanisms. Pretreatment with PPAR-a or PPAR-g activators decreased lipopolysaccharideinduced tumor necrosis factor (TNF)-a expression by myocytes, and may have played a role in inflammatory response in heart failure.

[59]

[60]

[61]

[15]

Ameliorated suppression of expansion and activation of myocardiogenic T cells; inhibited proinflammatory cytokine expressions in EAM PPAR-g ligands.

[63]

Cardioprotective effect due to the reduction of inflammatory response in the ischemic myocardium.

[64]

Anti-inflammatory effects independent of the insulin-sensitizing effect.

[17]

Decreased TNF-a and IL-6 protein levels, NAD(P)H oxidase activities in diabetes mellitus (DM), spontaneous hypertensive (SHR), and DM SHR hearts. Attenuated the inflammatory response in human cardiac AC16 cells exposed to the saturated fatty acid, palmitate, and mice fed a high-fat diet.

[29]

[66]

Ref., reference; EAM, experimental autoimmune myocarditis; LAD, left anterior descending artery; NAD(P)H, nicotinamide adenine dinucleotide phosphate.

rosiglitazone treatment decreased TNF-a, IL-6, and NAD(P)H activities in the cardiomyocytes [33]. These investigations indicate that PPAR-g activators may be a promising avenue for the treatment of CVD involving an inflammatory response. In addition, the cardioprotective effects of PPAR-g activators would benefit DM patients for whom CVD is a common lifethreatening complication. Nevertheless, high doses of PPAR-g agonists were shown to induce cardiac dysfunction with marked changes in the utilization of FFA and glucose [69]. Thus, the pathophysiologic mechanism on the cardiac effects of PPAR-g agonists causing an increased incidence of myocardial dysfunction has yet to be elucidated.

on FA-induced inflammation in the cardiomyocytes [70]. GW501516 was also found to reduce expression of the NF-kB target genes, MCP-1 and TNF-a in both human cardiac cells stimulated by palmitate and hearts of mice fed with a high-fat diet [70]. This implies that PPAR-d may counteract NF-kB activity. Therefore, activation of PPAR-d might be therapeutically useful as an anti-inflammatory agent in DM hearts.

5.3.

Previous studies have demonstrated that DM is associated with defects in contractility and ventricular dysfunction [71]. Moreover, DM has also been identified as an independent risk factor for developing atrial fibrillation (AF) with an increased

PPAR-d

Table 3 indicates that GW501516, selective PPAR-d ligand with 1000-fold higher affinity to PPAR-d, was evaluated for its effect

6. The role of PPAR-g ligands in cardiac electrophysiology and Ca2+ handling in DM and hypertension

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diabetes research and clinical practice 100 (2013) 330–339

Table 4 – Effect of peroxisome proliferator activated receptor (PPAR)-g agonists on cardiac electrophysiology. PPAR-g agonists

Study model

Dose/duration/route

Troglitazone

Guinea pig atrial myocytes

Troglitazone at 5, 10, and 30 mmol/ L for ICa,L

Troglitazone, rosiglitazone, pioglitazone

Domestic pigs weighing 24  1 kg

Rosiglitazone

Adult beagles of either sex

Troglitazone at 10 mg/kg/day, intravenously (i.v.) rosiglitazone and pioglitazone at 0.1 mg/kg, 1 mg/kg/day, i.v. Concentration-dependent effects of rosiglitazone at 1–100 mM

Rosiglitazone

Chinese hamster ovary cells expressing Kv4.3 channels Male DM WKY, SHR at 14 weeks age

Rosiglitazone

Pioglitazone

TG-PPAR-g mice at 10 weeks old

Rosiglitazone at 3, 10, 30, and 100 mM

Rosiglitazone at 5 mg/kg/day, per orem (p.o.)

Pioglitazone at 30 mg/kg, p.o.

Major cardiac findings 2+

Ref.

Inhibited voltage-dependent Ca currents; antagonized effects of isoproterenol in cardiac myocytes, and played a role in preventing diabetes mellitus (DM)-induced intracellular Ca2+ overload and myocardial changes. Blocked cardiac KATP channels at clinically relevant doses and promoted onset of ventricular fibrillations during severe ischemia.

[69]

Concentrations of >10 mM decreased the amplitude of phase 1 repolarization; reduced maximum velocity of depolarization causing plateau potential depression; concentration-dependently suppressed several transmembrane ion currents, under conventional voltage clamp conditions, and altered kinetic properties. Inhibited currents carried by Kv4.3 channels consistent with both open-channel blockage and acceleration of closed-state inactivation.

[72]

Significantly changed Ca2+ regulation and electrophysiological characteristics, and may have contained arrhythmogenic potential in DM rats with hypertension. PPAR-g overexpression induced action potential remodeling and caused acquisition of long-QT syndrome phenotype. PPAR-g agonist increased the incidence of complex ventricular arrhythmias and sudden death in TG-PPAR-g mice.

[74]

[71]

[73]

[75]

Ref., reference; ICa,L, L-type Ca2+ current; Ca2+, calcium; KATP, ATP-sensitive potassium; WKY, Wistar-Kyoto; SHR, spontaneously hypertensive rats; TG, transgenic.

risk of stroke [72]. Information on the mechanism of the cardiac effects of PPAR-g agonists causing the increased incidence of myocardial dysfunction in DM is limited. As can be seen in Table 4, troglitazone was previously observed to inhibit voltage-dependent calcium (Ca2+) currents that antagonize the effects of isoproterenol in guinea pig atrial myocytes [73]. Intracellular Ca2+ overload was also found to play an important role in the induction and/or maintenance of AF [74]. In an in vivo pig model, thiazolidinedione drugs were also shown to block cardiac ATP-sensitive potassium (KATP) channels at clinically relevant doses and promote the onset of ventricular fibrillation during severe ischemia [75]. Rosiglitazone in dog ventricular myocytes was found to cause action potential (AP) modification and concentration-dependent inhibition of the L-type Ca2+ current as well as transient outward and rapid delayed rectifier potassium currents [76]. Moreover, rosiglitazone was demonstrated to produce a concentration-dependent suppression of recombinant Kv4.3 channels involved in mediating the transient outward potassium current which significantly contributes to the early phase of repolarization of ventricular AP, thus providing mechanistic insights into the likely molecular basis of transient outward potassium current inhibition by the compound [77]. Rosiglitazone was also found to significantly change the Ca2+ regulation and electrophysiological characteristics in the ventricular myocytes, and may contain an arrhythmogenic potential in DM with hypertensive rodents [78]. Furthermore, transgenic PPAR-g-overexpressed mice

develop abnormal accumulation of intracellular lipids and die as young adults before any significant reduction in systolic function occurs, and were found to have QRS and QT prolongation intervals with spontaneous ventricular arrhythmias, including polymorphic ventricular tachycardia and ventricular fibrillations [79]. Additional studies using DM models would be of value to determine whether modification of PPAR-g agonists in these channels clinically affects the risk of arrhythmia at different drug concentrations.

7.

Conclusions

In the last decade, a substantial amount of evidence has accumulated relating to the roles of PPARs in the cardiac regulation of DM. Several in vitro and in vivo investigations have provided new concepts on how PPAR isoforms regulate energy and FA metabolism during pathologic states. PPAR-a overexpressed models, as well as PPAR-g-expression transgenes were both detrimental to cardiac functions. On the other hand, overexpression of PPAR-d has no harmful effects on cardiac function. It may be the imbalance of the expressions of PPAR-a, PPAR-g, and PPAR-d that contribute to CVD and cardiac dysfunction through both metabolic and non-metabolic pathways, new insight on the importance of metabolic derangements in the pathogenesis of CVD. Several investigations have also shown that the activation of PPARs exerts

diabetes research and clinical practice 100 (2013) 330–339

cardioprotective effects by inhibiting NF-kB, c-Jun, and AP-1 signaling pathways, thereby suppressing inflammatory responses. The roles of PPAR-a, PPAR-g, and PPAR-d during metabolic homeostasis differ a great deal in animal models. Although many mechanisms have been proposed, the exact mechanisms have not yet been fully elucidated. Further investigations are required in order to translate fundamental findings on the expression patterns of PPARs from animal studies to normal human hearts, as well as to examine diverse pathological states. In addition, given the potential adverse effects recently reported for thiazolinediones [60,80,81], careful studies are warranted to assess organ-specific metabolic and functional effects of PPAR agonists in normal human subjects and those with specific disease states.

Conflict of interest The authors declare that they have no conflicts of interest.

Acknowledgements The present work was supported by grants from Taipei Medical University-Wan Fang Hospital (100swf02 and 101wf-eva-02), the Center of Excellence for Clinical Trial and Research in Neuroscience of Wan Fang Hospital (DOH99-TD-B111-003), and grants from the National Science Council, Taiwan (NSC98-2314-B-010-031-MY3, NSC99-2314-B-016-034MY3 and NSC99-2628-B-038-011-MY3).

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