Retinoid metabolism and its effects on the vasculature

Biochimica et Biophysica Acta 1821 (2012) 230–240

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a l i p

Review

Retinoid metabolism and its effects on the vasculature☆ Eun-Jung Rhee a, b, Shriram Nallamshetty a, c, Jorge Plutzky a,⁎ a b c

Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Cardiovascular Division, Massachusettes General Hospital, Harvard Medical School, Boston, MA, USA

a r t i c l e

i n f o

Article history: Received 29 March 2011 Received in revised form 15 June 2011 Accepted 6 July 2011 Available online 23 July 2011 Keywords: Retinoid Vascular smooth muscle cell RXR RAR Inflammation Atherosclerosis

a b s t r a c t Retinoids, the metabolically-active structural derivatives of vitamin A, are critical signaling molecules in many fundamental biological processes including cell survival, proliferation and differentiation. Emerging evidence, both clinical and molecular, implicates retinoids in atherosclerosis and other vasculoproliferative disorders such as restenosis. Although the data from clinical trials examining effect of vitamin A and vitamin precursors on cardiac events have been contradictory, this data does suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical animal model and cellular studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways. In addition, established retinoid effects on lipid metabolism and adipogenesis may indirectly influence inflammation and atherosclerosis. Collectively, these observations underscore the scope and complexity of retinoid effects relevant to vascular disease. Additional studies are needed to elucidate how context and metabolite-specific retinoid effects affect atherosclerosis. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Atherosclerosis is a common pathologic feature in many metabolic diseases including obesity, metabolic syndrome, and type 2 diabetes (T2D). The threat for diabetic vascular disease is increasingly evident at both ends of the life span: in younger patients as a result of the obesity epidemic as well as in the aging population [1].While much progress has been seen in the detection, treatment, and prevention of atherosclerotic complications, the morbidity and mortality that result from vascular injury and atherosclerosis, especially in the setting of

metabolic abnormalities, remain major issues. As such, efforts persist at finding novel mechanisms and new potential therapeutic targets in cardiometabolic diseases. One such area of interest is that of retinoid metabolism and the role of retinoid-activated receptors in transcriptional regulation relevant to vascular disorders. Retinoic acid (RA), the active metabolite of vitamin A (retinol), is a critical signaling molecule during vertebral development [2]. Retinoids are recognized as crucial factors in controlling cellular differentiation and developmental programs. Retinoids also exert functional effects on vision, growth, reproduction, and resistance to infection. Vitamin A is an

Abbreviations: ADH, alcohol dehydrogenase; ADMA, asymmetric dimethylarginine; AP-1, activated protein-1; apo14, β-apo-14′-carotenal; ARVM, adult rat ventricular myocytes; ATBC, Alpha-tocopherol Beta-carotene Cancer Prevention Study; atRA, all-trans retinoic acid; BCO-I, β,β-carotene-15,15′-monooxygenase; BCO-II, β,β-carotene-9′,10′dioxygenase; bFGF, basic fibroblast growth factor; CARET, Beta-Carotene and Retinol Efficacy Trial; CAD, coronary artery disease; CMEC, cultured microvascular endothelial cells; CRABP, cellular retinoic acid binding protein; CRBP, cellular retinol binding protein; CRP, C-reactive protein; CYP26, cytochrome P450 family 26; DBD, DNA binding domain; DC, dendritic cell; eNOS, endothelial nitric oxide synthase; ESC, embryonic stem cells; FXR, farnesoid X receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HAT, histone acetyltransferase; HDAC, histone deacetylase; HUVEC, human umbilical vein endothelial cell; IL, interleukin; iNOS, inducible nitric oxide synthase; KLF, Krüppel-like zincfinger transcription factor 5; LBD, ligand binding domain; LPS, lipopolysaccharide; LXR, liver X receptor; mfn-2, mitofusin 2; MGP, matrix Gla protein; MHC, major histocompatibility complex; miR, microRNA; NOS, nitric oxide synthase; OPG, osteoprotegerin; PAI-1, plasminogen activator inhibitor-1; PDGF, platelet-derived growth factor; PKC, protein kinase C; PMA, phorbol-12-myristate-13-acetate; PPAR, peroxisome proliferator-activated receptor; PRIME, Prospective Epidemiological Study of Myocardial Infarction; RA, retinoic acid; RALD, retinaldehyde; RALDH, retinaldehyde dehydrogenase; RANKL, receptor-activator of NF-κB; RAR, retinoic acid receptor; RARE, retinoic acid response element; RARRES1, retinoic acid receptor responder-1; RBP, retinol-binding protein; RXR, retinoid X receptor; SDR, short-chain dehydrogenases/reductases; T2D, type 2 diabetes mellitus; TH-cell, helper T cell; TNF, tumor necrosis factor; tPA, tissue plasminogen activator; tTG, tissue transglutaminase; TTR, transthyretin; VCAM, vascular cell adhesion molecule; VDRE, vitamin D response element; VSMC, vascular smooth muscle cell ☆ This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism. ⁎ Corresponding author at: 77 Ave. Louis Pasteur, NRB 742, Boston, MA 02115, USA. Tel.: +617 525 4360. E-mail address: [email protected] (J. Plutzky). 1388-1981/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2011.07.001

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essential vitamin that must be derived from vitamin-A-rich foods as well as foods containing the preformed carotenoid β-carotene, which is composed of two retinol molecules [3]. Vitamin A deficiency causes impaired cellular differentiation, reduced resistance to infection, anemia and even death. Indeed, in studies published as early as 1925, rats deprived of dietary vitamin A manifest increased epithelial growth, including neoplastic responses [4]. Conversely, many aquatic species like sharks may be protected from cancer as a result of their high vitamin A content [5]. Currently, RA is a primary treatment for acute promyelocytic leukemia [6]. Importantly, many of these retinoid-regulated cellular responses, such as cell growth and differentiation, are also central to vascular injury and atherosclerosis. Similarly, increasing evidence highlights cellular overlap between adipocytes and macrophages as well as clinical connections between obesity and cardiovascular disease. These issues raise fundamental questions regarding the part retinoid metabolism and retinoid receptors play in atherosclerosis and cardiovascular disease in general. Although this is an area of burgeoning interest and considerable future potential, the data in this arena is fairly limited. In this review, we will consider recent advances in retinoic acid metabolism and its relationship with atherosclerosis and vascular disorders [7,8]. 2. Overview of retinoid metabolism A detailed overview of retinoid metabolism is beyond the scope of this article and is reviewed extensively elsewhere, including in this series. Despite this, several salient features of the retinoid axis are worth noting as a basis for the issues considered here. Since retinoids cannot be synthesized de novo by humans, retinoids become of obvious interest as nutrient-derived biologically-active mediators that might help link diet, obesity, and cardiovascular disease. Retinol, or vitamin A, can be provided as retinyl ester, as found in milk, liver, and eggs, or as a provitamin in the form of carotenoids, for example in carrots or red pepper. In these sources, β-carotene represents the most efficient precursor for RA formation [3]. The predominant natural circulating retinoid is retinol, which is present at micromolar levels and derived from the carotenoid β-carotene (provitamin A) and retinyl ester, stored primarily in liver as retinyl palmitate. Retinol and retinyl esters are precursors for active retinoid isoforms, including all-trans, 11-cis, 13-cis, 9,13-di-cis, 9-cis, and 11,13-di-cis, with all-trans retinol being the predominant form. Retinol is bound to retinol-binding protein (RBP) in circulation and its plasma levels are homeostatically regulated. All-trans RA (atRA) is a small lipophilic molecule (300 Da) that circulates in plasma bound to albumin at a concentration of 1 to 10 nmol/L [9,10]. Two RA isomers have been identified in vivo: 9-cis RA and 13-cis RA (Fig. 1). The physiological function of 13-cis RA, which is detected at significantly lower concentrations in both mice and humans, remains unclear [11,12]. The retinoid 9-cis RA binds to the retinoid X receptor (RXR) with high affinity, at least in vitro [13,14]. However, 9 cis-RA has not been demonstrated in vivo. AtRA is generated from the parent vitamin A molecule all-trans-retinol by two consecutive oxidation steps: oxidation from retinol to retinaldehyde (RALD), and then RALD to RA (Fig. 2). These oxidation steps are mediated by retinol dehydrogenases and retinaldehyde dehydrogenases (RALDH). Three distinct isoforms of RALDHs of the ALDH1A class exist in vertebrates (ALDH1A1 or RALDH1, ALDH1A2 or RALDH2, and ALDH1A3 or RALDH3) and one RALDH of ALDH8 class called RALDH4 [15]. Two classes of enzymes function as retinol dehydrogenases, at least in vitro: medium-chain alcohol dehydrogenases (ADH) and short-chain dehydrogenases/reductases (SDRs) [15]. There are 5 classes of ADH that exist in both mice and humans, and in adult tissues, retinol is metabolized by ADH1, ADH3, and ADH4 [16]. Retinoids exert their biological effects by activating specific members of the steroid hormone nuclear receptor family, including the retinoic acid receptor (RAR) and RXR (Fig. 2). RARs α, β and γ bind

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both atRA and 9-cis RA with high affinity, while RXR α, β and γ only bind avidly to 9-cis RA. The retinoid 13-cis RA is not a ligand for retinoid receptors, but can be readily converted to one. RARα, RXRα, and RXRβ are ubiquitously expressed, whereas RARβ, γ, and RXRγ exhibit tissue-restricted patterns of expression [17–20]. RXRs regulate transcription as either a homodimer or as an obligatory heterodimeric partner for various other subclass I nuclear receptors, including RARs, peroxisome proliferator-activated receptors (PPARs), the vitamin D receptor, thyroid hormone receptors, the farnesoid X receptor (FXR), and the liver X receptor (LXR). In the absence of ligand, RXR forms homotetramers that are transcriptionally inactive but rapidly dissociate into active dimers upon ligand binding [21–23]. Thus, RARs and RXRs help maintain homeostasis and function as nutrient and metabolite sensors either directly, through their own action, or as a necessary partner for the other key transcriptional regulators [24,25]. Like other RXR partners, the RAR/RXR heterodimer forms on two interfaces, namely the ligand binding domain (LBD), and the DNA binding domain (DBD). The complex then interacts with specific response elements in the regulatory regions of target genes. RARαdeficient mice show features of vitamin A deficiency, with decreased viability, growth deficiency, and male sterility [26]. Most of these defects are reversed by RA treatment. RARβ-deficient mice exhibit a selective loss of striosomal compartmentalization in the rostal striatum in the central nervous system and locomotor defects, implicating retinoids in brain function [27,28]. RARβ is a direct target of RA-induced gene expression and highly activated by exogenous retinoid treatment. RARγ is highly expressed in the skin. RARγ null mice also display some vitamin A deficiency defects that are rescued by RA treatment [29,30]. Observations from mice deficient in a single RAR isotype suggest functional redundancy among RARs. In contrast, RAR double mutants die either in utero or shortly after birth and display multiple congenital abnormalities associated with vitamin A deficiency [26]. All three RXRs have also been studied using mouse deficiency models [31]. RXRα inactivation is embryonically lethal with hypoplastic development of cardiac ventricular chambers and ocular malformations. These defects are also observed in vitamin A deficiency models, implicating RXRα in retinoid signaling in vivo [32]. RXRβ deficiency resulted in 50% perinatal lethality [33]. Compound RXR-deficient mice reveal that one RXRα copy is sufficient to perform most RXR functions [34]. 3. Retinoic acid in atherosclerosis — clinical perspective Studies testing retinoid effects on human cardiovascular events were initiated decades ago given data showing vitamin A involvement in angiogenesis, cellular growth and oxidative balance. However, the results of clinical trials examining the effects of various forms of retinoids on cardiovascular events and mortality have been conflicting. β-carotene's purported antioxidant effects stimulated many cardiovascular studies. In a nested control study among 25,000 Americans, an inverse relationship was seen between β-carotene levels and subsequent myocardial infarction (MI); the excess risk of MI associated with low serum carotenoids level was limited to smokers [35]. In the Physicians' Health Study, β-carotene supplementation (50 mg) on alternate days showed neither benefit nor harm in terms of the incident cardiovascular disease or all cause mortality [36]. The Alpha-tocopherol Beta-carotene Cancer Prevention (ATBC) Study, involving 29,133 male smokers aged 50–69, investigated the effects of alpha-tocopherol and β-carotene supplements on the incidence of lung cancer. In this study, the risk of fatal coronary heart disease increased in those receiving either β-carotene or the combination of α-tocopherol and β-carotene [37]. In the Women's Health Study, there was neither benefit nor harm from β-carotene supplementation on cancer or cardiovascular disease [38].

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A

B

Diet

Liver

β-carotene

Retinyl esters

Retinol-CRBP

cleavage asymmetrical

BCO-II

symmetrical

Vitamin A (Retinol)

BCO-I

Apocarotenal

Blood Retinol-RBP-TTR

ADH/SDR Retinaldehyde RALDH 1-4

CRABP Apocarotenoic acid

CYP26

Retinoic acid

Co-activator HAT

Oxidized metabolites

transcription

RXR-RAR Co-repressor HDAC

transcription

RXR-RAR Fig. 1. Retinoids and their metabolism. A. Structures of key retinoids, the metabolites of retinol, are provided. Retinoids constitute a diverse group of structurally related compounds that have distinct and divergent effects. B. Vitamin A is supplied to the body from dietary sources or from retinol derived from retinyl ester stores in the liver. Retinoic acid is generated through two oxidation steps: 1) retinol is converted to retinaldehyde by alcohol dehydrogenases (ADH) or short-chain dehydrogenases/reductases (SDR); and 2) retinaldehyde is converted to retinoic acid by retinaldehyde dehydrogenase (RALDH). Retinoic acid exerts its biologic effects through the specific retinoid receptors, RXR and RAR.

The Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study provided 5 years of follow-up in 9758 men from France and Northern Ireland who were free of coronary heart disease at baseline. In this cohort, the relative risk of coronary artery disease in the lowest quintiles for plasma retinol levels was 2.65 fold higher than those in the highest quintiles for plasma retinol level [38]. Conflicting results on the effects of retinoids on cardiovascular events also exist. The Beta-Carotene and Retinol Efficacy Trial (CARET), a randomized lung cancer chemoprevention trial, was terminated 21 months early due to the unexpected findings that the active β-carotene and retinyl palmitate (25000 IU) daily treatment group had a 28% higher incidence of lung cancer and a 46% higher

mortality rate than controls [39]. Cardiovascular death was also increased 26% by active treatment. Analysis of the CARET data to investigate the increased cardiovascular mortality found significantly higher total cholesterol and triglyceride levels with vitamin A alone or in combination with β-carotene supplementation. However, these changes do not likely fully explain the increased cardiovascular mortality in CARET [40]. Finally, in a meta-analysis that included 68 randomized trials with 232,606 participants from the primary and secondary prevention trials in adults randomized to receive β-carotene, vitamin A, vitamin C, vitamin E, or selenium versus placebo or no intervention, β-carotene and vitamin A supplements, either alone or in combination, significantly increased mortality [41]. Although this

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RA effects in Vascular Smooth Muscle Cell Cell migration - Migration rate ↓(↑?)

Phenotypic diversity

Cell proliferation - Proliferation ↓↑→

Cell differentiation

- β1-integrin↑

- Suppressed proliferation with mitogenic stimuli - Activated proliferation in quiescent conditions - Inhibit ATII-induced proliferation

- SM-MHC ↑ - α-actin ↑

- Increase KLF4 acetylation - increase miR-10a expression in ESC

Fibrinolysis/coagulation - Increase PAI-1

Cell apoptosis - Regulate intrinsic pathway (bcl-2, caspases) - Regulate extrinsic pathway (Fas/FasL) - SMCs from different layer (medial or intimal) have different responses

Vascular calcification - Increase Matrix Gla protein ↓(↑?) - increaed OPG/RANKL ratio

Fig. 2. Pleiotropic effects of retinoic acid on vascular smooth muscle cell function and atherosclerosis. Retinoic acid shows variable effects on multiple aspects of vascular smooth muscle cell function relevant to the development and progression of atherosclerosis including cell migration, differentiation, apoptosis, phenotypic diversity, fibrinolysis, and vascular calcification.

dataset remains controversial, these findings may reflect the importance of retinoids, and the complexity of their impact on clinical outcomes, which may be driven by factors like the nature of specific retinoids or genetic aspects of their metabolism. Recently, Kraan et al. [42] suggested a relationship between retinoids and altered gene expression in circulating CD34+ cells in coronary artery disease (CAD). When whole genome transcriptome analysis of CD34+ cells was performed in 12 CAD patients and 11 matched controls, the data suggested RA programmed circulating CD34+ cells in CAD patients towards a reduced capacity to migrate to ischemic tissues. In a prior study, the retinoic acid receptor responder1 gene (RARRES1) was shown to be more highly expressed in unstable carotid endarterectomy plaque specimens [43]. These data suggest that RA may modulate atherosclerosis in humans by altering gene expression. These results, combined with the clinical studies discussed earlier, suggest that retinoid effects on cardiovascular disease are important, but better understanding of the basic science involved in response to retinoids is required. 4. Retinoic acid metabolism in the vasculature Several key enzymes involved in retinoid action and metabolism exist in the vasculature. ADH, which converts retinol to RALD, is expressed in rat and human arteries and veins [44]. The distribution of ADH activity in human aorta was 23.5% in intima, 74% in media, and 2.5% in adventitia; in most samples, class I ADH was the only form responsible for the activity seen. In contrast, rat blood vessels showed class IV, but not class I, ADH expression in endothelium and media, suggesting different ADH isoforms may promote retinol oxidation in different species. In addition, all the retinoid receptors except RXRγ are expressed in cultured smooth muscle cells (SMC) and aortas [45]. Transiently transfected reporter gene assays in SMCs also indicate retinoid receptor activity. Among the cytochrome P450 enzymes that catabolize RA, CYP26B1 is constitutively expressed in rat and human aortic smooth muscle cells [46,47]. In addition, inhibition of CYP26B1 gene expression using siRNA or chemical inhibition of CYP26B1 enzymatic activity both increased atRA-mediated signaling and decreased cell proliferation. Thus, CYP26B1, by regulating atRA metabolism, may influence important SMC signaling pathways [46,47].

5. Retinoic acid and vascular development One setting in which retinoid importance has been clearly established is in development, including formation of the vasculature and heart. Vitamin A-deficient (VAD) rat models displayed specific aortic arch and ventricular septal defects [48]. In addition, genetic deletion of one specific isoform of the RAR family does not cause developmental defects, demonstrating redundancy between receptor subtypes [49,50]. In contrast, compound null mutations of RAR genes lead to significant heart malformations [51,52]. RXRα gene disruption results in prominent cardiac defects, including hypoplasia of the ventricular compact zone and muscular ventricular septal defects [53–55]. Interestingly, the hearts of RXRβ and RXRγ knockout mice develop normally. Compound mice deficient in both RXRα and RXRγ exhibited the same cardiac and ocular defects found in RXRα null mutants, suggesting that one copy of RXRα is sufficient for most of the functions of the RXRs in the context of vascular and cardiac development [34]. Also, compound null mutations of RXRα with RARs display marked synergistic effects in terms of the defects seen [32,54]. A recent study also supports a role for RA in coronary vessel formation. Early high levels of RA and VEGF prevent coronary SMC differentiation from epicardially derived cells before the endothelial network is formed, suggesting that RA influences the formation of the complex tree of coronary vessels [56]. 6. Retinoids and their effects on vascular injury and atherogenic responses — evidence from pre-clinical studies In vivo evidence suggests that retinoids may influence arterial responses to injury and atherogenesis. It is important to note that the processes of arterial injury, as might occur during coronary stenting, and that of atherosclerosis, are not the same although some overlap does exist in terms of these processes. Several studies tested the effect of atRA on intimal hyperplasia/restenosis after vascular intervention in animal models. Miano et al. [57] found that oral atRA administered for 4 days significantly reduced neointimal area in a rat common carotid artery balloon injury model. AtRA-treated rats had 35% to 37% higher luminal area in the injured vessels compared with controls. Neuville et al. [58] showed that atRA inhibited proliferation and increased SMC migration at the site of vascular injury. AtRA also

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decreased the SMC marker α-smooth muscle actin, consistent with decreased SMC differentiation. These investigators also found that RARα, but not RXR agonists inhibited SMC proliferation and reduced carotid intimal hyperplasia. Lee et al. [59] showed that atRA administration for 14 days after balloon injury of rat aorta increased re-endothelialization and endothelium-dependent vaso-relaxation of injured aorta. In these studies, the neointimal area was significantly less in atRA-treated versus control groups, implicating the atRA in post-injury endothelial recovery. Retinoid treatment also limits restenosis [60,61] in various other animal models [60,62,63], and after local administration [64]. Collectively, these investigations suggest that retinoids favorably modulate SMC migration and proliferation, and re-endothelialization following vascular injury. Pre-clinical studies examining the effects of retinoids on experimental atherosclerosis independent of vascular injury and diet-induced atherogenesis are more limited, but in general support a cardioprotective effect through retinoids. Harari et al. [65] demonstrated that 9-cis β carotene-supplemented diets inhibited high-fat diet induced hypercholesterolemia and atherosclerosis in low-density lipoprotein receptor (LDL-R) deficient mice. In addition, RA suppressed foam cell lesion formation in Chlamydia pneumoniae-infected hyperlipidemic C57BL/6J mice on an atherogenic diet [66]. Further, Takeda et al. showed that Am80, a RARα/β synthetic agonist, reduced atherosclerotic lesion formation in the aortas of Apoliporotein E-deficient mice [67]. Clearly this is an area in need for further research. 7. Retinoids and VSMC migration, proliferation and differentiation Vascular smooth muscle cell (VSMC) growth, differentiation, and migration play an important role in atherosclerosis and restenosis after revascularization [68]. During the early stages of vascular injury, medial VSMCs migrate to the intima where they promote extracellular matrix deposition and reduce lumen size [69]. The switch from a contractile to synthetic SMC phenotype, with decreased expression of SMC differentiation markers, may be central to the arterial response to injury [70]. Recent evidence also demonstrates that VSMC apoptosis may promote intimal hyperplasia and plaque formation and progression [71]. Thus, VSMCs are the key players in the normal vessel wall and in pathologic responses to injury and atherosclerosis. Retinoids may modulate VSMC behavior and function relevant to atherosclerosis and restenosis. In injured VSMCs, α1β1 integrin is the major collagen receptor expressed and may mediate collagen matrix reorganization [72]. Retinoids induce β1-integrin expression and levels [73]. Retinoids can increase the expression of tissue plasminogen activator (tPA), a facilitator of cellular migration [58] and have been implicated in increasing SMC migration [58,74]. However, other studies report retinoid-mediated decreases in VSMC migration [75,76]. These contradictory results emphasize the complex characteristics of retinoid regulation of VSMC biology in atherogenesis and vascular injury responses. Retinoids may also control VSMC proliferation, another major factor in vascular responses to injury. Peclo et al. [77] reported that atRA treatment in cultured rat aortic SMC enhanced cellular proliferation. Hagiwara et al. [78] reported that atRA inhibited the proliferation of mouse chondrocytes and osteoblasts without rat SMC effects. In general, RA appears to limit VSMC proliferation across different species [45,79,80]. Despite this, retinoids show divergent and complex effects in the regulation of VSMC mitogenesis in other contexts [81]. For example, in rat aortic SMCs, atRA stimulation alone increased cell number and mitogenesis. However, when the cells were stimulated with atRA in the presence of a mitogenic stimulus, cell number was reduced and proliferation suppressed. Thus, RA-induced responses may differ depending on whether a cell is quiescent or in a growth-stimulated state. In general, retinoids inhibit SMC proliferation induced by mitogenic factors such as platelet-derived growth

factor-(PDGF)-BB [45], angiotensin II [82], serotonin [83], endothelin1 [81], and basic fibroblast growth factor (bFGF) [84]. These RA effects appear to be cell cycle-dependent, involving cyclins and cyclindependent kinases [80,81,84]. The pleiotropic effects of retinoids on VSMC proliferation may also be mediated through effects on angiotensin II. Angiotensin II promotes proliferation and hypertrophy of VSMCs, induces vascular inflammation and extracellular matrix deposition, thereby promoting hypertension, arteriosclerosis and vascular damage [85,86]. Angiotensin II activates cell proliferation through the activator protein-1 (AP-1) complex by induction of proto-oncogene expression [87]. Haxsen et al. [82] reported that exposure of rat aortic SMCs to atRA dose-dependently inhibited angiotensin II-induced cell proliferation. Also, angiotensin-II induced expression of c-fos was abrogated by atRA treatment. AtRA treatment downregulated AT1 receptor mRNA levels, suggesting retinoids might interfere with angiotensin-II mediated VSMC proliferation. Retinoids may play an important role in regulating apoptosis [88]. The SMC population in the arterial wall, including lesions, is determined by the balance between SMC proliferation, apoptosis, and cell death [71,89]. Apoptosis in SMCs contributes to intimal hyperplasia and plaque evolution. RA regulates intrinsic apoptotic pathways by controlling expression of certain apoptosis-related genes, such as, bcl-2 and caspases, as shown in cancer cell lines [90,91]. Furthermore, RA also modulates extrinsic apoptotic pathways through Fas/FasL system [92,93]. Ou et al. [94] reported RA involvement in VSMC programmed cell death through the regulation of tissue transglutaminase (tTG), a protein involved in apoptotic body formation. Interestingly, SMCs from the media or intima may have different apoptotic responses to RA [95]. Functional VSMC responses are influenced by VSMC phenotype. Both contractile and synthetic states have been described based on cellular morphology, expression levels of SMC marker genes, proliferative potential, and migration properties [76]. Krüppel-like zinc-finger transcription factor 5 (KLF5) is a transcription factor induced in activated VSMC [96]. KLF5 regulates expression of the SMemb/NMHC-B gene, a molecular marker of phenotypically modulated VSMCs. VSMC outgrowth from human arterectomy specimens in vitro was associated with increased KLF5 expression [97]. The heterozygous KLF5-deficient mouse has diminished arterial wall thickening and angiogenesis [98]. RAR ligands can repress KLF5 transcriptional activity, consistent with retinoid-mediated growth inhibition of activated VSMCs. Retinoids may also increase expression of the major histocomptability complex (MHC), a contractile SMC marker [75], and α-actin [61], although contradictory results exist [58]. When rat aortic rings were cultured with atRA, the effects of contractile antagonists were inhibited, suggesting atRA might help maintain contractile function [99]. Consistent with this, vitamin A-deficient mice showed reduced contractile function compared with controls, with repression of contractile-related proteins such as α-actins [100]. The synthetic RARα agonist Am80 reportedly inhibits expression of KLF5, which as noted may modulate post-injury VSMC phenotypes. In addition, Am80 inhibited serum-induced repression of SMC α-actin and MHC, again suggesting retinoids in maintenance of the contractile SMC phenotypes after vascular injury. KLF4 may also modulate VSMC phenotype. AtRA treatment in rat aortic SMCs induces KLF4 through a p53-dependent mechanism, with increases in VSMC differentiation marker genes such as SM22α and SM α-actin [101]. Furthermore, KLF4 repression by siRNA abrogated these atRA effects, implicating KLF4 as a determinant of retinoid actions in VSMCs. AtRA also induces KLF4 acetylation by p300 and increases the ability of KLF4 to transactivate the expression of mitofusin 2 (mfn-2), a mitochondrial fusion protein that limits VSMC proliferation [102]. More recently, microRNAs (miR) have been implicated in VSMC differentiation and function [103]. MicroRNA profiling showed that miR-10a expression steadily increased during in vitro differentiation of mouse embryonic stem cells (ESCs) into SMCs. Using a miR-10a inhibitor, miR-10 was found to be a critical mediator in RA-mediated

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SMC lineage determination. RA also induced expression of NF-κB target genes including miR-10a in ESCs. Taken together, retinoid metabolites exert important effects on multiple VSMC responses relevant to atherosclerosis and injury, including differentiation and migration. The sometimes contradictory nature of the data in this area underscores the complexity of the retinoid system, and the need to better understand the relationship between retinoid biology and VSMC responses. 8. Retinoids and the fibrinolysis/coagulation system Several lines of evidence demonstrate that retinoids have important effects on the coagulation system that are directly relevant to atherosclerosis. RA administration attenuates pro-coagulant properties (Figs. 3). Retinoids may promote fibrinolysis by inducing tPA [58,104– 106]. A retinoic acid response element (RARE) is present in the promoter of the tPA gene, suggesting direct transcriptional regulation [107]. However retinoids also increase PAI-1 (plasminogen activator inhibitor1) expression in VSMCs, raising questions regarding RA's net effects in the vessel wall [108]. Retinoids may also decrease the coagulant properties of vessels [109]. Retinoids reportedly inhibit tissue factor [110], and also suppress the expression of the vasoconstrictor thromboxane A2 [111]. Overall, retinoids appear to prevent thrombosis through increased fibrinolytic activity and decreased pro-thrombotic processes in vessel wall. 9. Retinoids and inflammation Inflammation, including both innate and adaptive immune responses, is involved in all stages of development of atherosclerosis [112–114]. Rats deficient in vitamin A exhibit increased inflammatory responses [115]. Vitamin A and atRA modulate host susceptibility to infection by interfering with both innate and adaptive immune function as well as host inflammatory responses [116]. RA enhances cytotoxicity and T-cell proliferation [117]. Vitamin A-deficient mice have defects in helper T cell (TH-cell) activity [118]. In addition, RA inhibits B-cell proliferation [119,120], although evidence for opposite effects also exist [121,122]. RA may also inhibit B-cell apoptosis

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through RAR responses [123], and modulate antigen presentation by exerting direct effects on dendritic cells (DC) function. For example, RA increases the expression of matrix metalloproteinases [124]. In addition, in the presence of inflammatory stimuli such as TNF-α, RA enhances DC maturation and antigen-presenting capacity via RXR receptors [125]. Retinoids also modulate the expression of numerous inflammatory cytokines. In human monocytes, RA suppressed the granulocytemacrophage colony-stimulating factor (GM-CSF)-induced production of activin A [126]. In contrast, RA induced interleukin (IL) 1β production and inhibited IL-1 receptor antagonist expression in phorbol-12-myristate-13-acetate (PMA)-activated monocytes [127]. In macrophages, RA inhibited endotoxin, IFN-γ, and phorbor esterinduced tumor-necrosis factor (TNF) production [128]. Also, in lipopolysaccharide (LPS)-stimulated macrophages, RA was found to inhibit IL-12 production [129]. In general, these studies suggest that RA may limit inflammation by repressing chemokine production. Recent work also implicates retinoids in regulating endothelial adhesion molecule expression, an inflammatory response involved in early stages of atherogenesis [130]. RA suppresses TNF-stimulation of vascular cell adhesion molecule (VCAM)-1 in endothelial cells, with reduced VCAM-I dependent T cell binding [131]. In contrast, the stimulation of human endothelial cells with β-apo-14′-carotenal (apo14), a specific product of asymmetrical β-carotene cleavage, increased VCAM-1 mRNA expression and reversed the known repressive effects of activation of the PPARα pathway on TNFα-stimulatedVCAM-1 mRNA expression [132]. In addition, in immortalized human aortic endothelial cells, TNF-α and 9-cis-RA synergistically enhanced ICAM-1 protein expression via the functional interaction of NF-κB p65 homodimers with RAR/RXR heterodimers [130]. C-reactive protein (CRP) is an inflammatory biomarker associated with increased cardiovascular risk [133]. CRP production is regulated primarily by IL-6 in liver [134], CRP production may also occur in situ in vascular lesions [135]. RA is known to antagonize NF-IL6, a transcription factor involved in regulating IL-6 production [136]. An inverse relationship has been observed between retinol and CRP levels during inflammation [137]. These various studies also establish the role of retinoids in inflammation, and the specific functional

Fig. 3. The role of retinoic acid in atherogenesis. Retinoic acid has diverse effects in the arterial wall. In the intima, retinoic acid influences nitric oxide synthesis and function through the modulation of synthetic enzymes. Retinoic acid also affects the expression of angiotensin II and adhesion molecules in the intima. In the media, retinoic acid modulates smooth muscle cell proliferation, differentiation, apoptosis and phenotypic diversity. Retinoic acid also influences other systemic processes relevant to atherosclerosis including fat metabolism and inflammation.

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effects on vascular disease and atherosclerosis. The mechanisms for those effects remain to be established. 10. Retinoic acid and vascular calcification Given that retinoids modulate skeletogenesis and post-natal bone metabolism, retinoids may also be involved in vascular calcification. Vascular calcification involves the intima, media, and adventitia of the artery [138]. Vascular calcification correlates directly with increased cardiovascular mortality [139]. Furthermore, the calcification process in an artery is regarded not as a passive phenomenon, but as an active process characterized by the formation of an osteogenic milieu within the vessel wall [140]. RA regulates chondrocyte maturation and mineralization. In osteoblasts, atRA treatment of the human MG-63 osteosarcoma cell line dose-dependently increased osteoprotegerin (OPG)/receptoractivator of NF-κB ligand (RANKL), major proteins in bone resorption [141]. Given that the OPG/RANKL system helps balance bone resorption and vascular calcification, this finding may be a clue to the effect of RA on vascular calcification. High vitamin A intake may promote vascular calcification [142]. Variable effects have been seen with RA on matrix Gla protein (MGP), an inhibitory factor for calcification highly expressed in VSMC, fibroblasts, chondrocytes, and osteoblasts [143,144]. Some studies report RA increases MGP while others find repression, for example in rat kidney cells, human breast cancer cells, and rat VSMC [145,146]. In the human breast cancer cell line MCF-7 and the rat kidney cell line NRK52E, these MGP reductions were via RAR and RXR [146]. Fu et al. [147] found that 9-cis-RA mitigated 1,25(OH)2D3-induced renal calcification by modifying the 1,25(OH)2D3-induced increase in uncarboxylated MGP in mice. In that study, the attenuation of 1,25 (OH)2D3-induced MGP expression in the kidney could be due to the interaction between vitamin D receptor and RXR, because both are required for binding to vitamin D response element (VDRE) in the promoter of the target genes. The effect of 9cis-RA on MGP expression through the interaction of vitamin D receptor and RXR could be one plausible mechanism that explains the effect of RA on vascular calcification. Further studies are needed in order to understand how different retinoid metabolites and retinoid-activated receptors modulate vascular calcification. 11. The effect of retinoic acid on endothelial function The endothelium is now recognized as a dynamic organ with endocrine, paracrine, and autocrine effects directly related to atherosclerosis. Relatively little is known about the role of retinoid metabolism and endothelial responses. RA can attenuate activation of inducible nitric oxide synthase (iNOS) 2, an important component of the innate immune response, in various cell types in vitro [148]. In cultured microvascular endothelial cells (CMEC) and adult rat ventricular myocytes (ARVM), RA treatment significantly attenuated iNOS2 expression after LPS and/or cytokine-stimulation. However, the effect of RA on LPS-induced NOS2 expression showed somewhat contradictory results between in vitro and in vivo experiments [149]. This group also showed that atRA activates NOS2 through RARα but not RXR in rats. NO is a potent vasodilator and signal modulator molecule. Endothelium-derived NO plays important roles in controlling vascular function. atRA increases NO synthesis by endothelial cells by altering endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) [150]. Uruno et al. [151] demonstrated induction of NO production by atRA in various endothelial cell types, and that these increases were by endothelial NO synthase (eNOS) phosphorylation through RAR-mediated PI3K/Akt pathway activation. AtRA also induced angiogenesis via RAR by stimulating human umbilical vein endothelial cell (HUVEC) proliferation, enhancing endogenous VEGF signaling, and inducing hepatocyte growth factor and angiopoietin-2

production in a HUVEC/normal human dermal fibroblast coculture model, suggesting retinoids as a possible therapeutic angiogenesis intervention [152]. In contrast, Salazar et al. [153] reported that exposing endothelial cells to 13-cis-RA produced significant changes in the expression of genes implicated in cell adhesion and in lipid metabolism, suggesting that 13-cis-RA might have deleterious effects on atherosclerosis. RA increased expression and activity of prostaglandin I2 via RAR [154]. Recently, Chai et al. [155] reported 9-cis-RA effects on high-glucose-induced oxidative stress in HUVECs. Stimulating endothelial cells with 9-cis-RA significantly inhibited highglucose-induced oxidative stress and expression of Nox4, gp91phox, and p22phox, the components of nicotinamide adenine dinucleotide phosphate oxidase. These effects were through inhibition of Rac-1 activation, with 9-cis-RA rapidly inhibiting glucose-induced activation of protein kinase C (PKC), an upstream activator of Rac-1 activation. These results show that RXR ligands might have cardioprotective effects by antagonizing PKC in HUVECs. 12. Retinoid actions on metabolism may influence atherosclerosis indirectly Retinoid metabolism may also influence atherosclerosis indirectly through its action on lipid metabolism and adipogenesis. Vitamin A deficiency favors fat deposition [156]. Extensive evidence establishes that RAR and RXR are involved in adipogenesis. For example, during adipogenesis, RXR expression patterns vary considerably, and the effects of atRA versus 9-cis-RA also vary depending on when cells are stimulated [157]. RAR is also involved in adipogenesis [158]. In RARoverexpressing cells, RA stimulation inhibits differentiation of 3T3-L1 cells during early stages of adipogenesis but not when added 48 hours after differentiation had been initiated. Thus, although RA inhibits adipocyte differentiation in certain stages, the effect could vary as a function of timing or expression levels of transcriptional factors and other mediators. RALD has been primarily considered merely as a precursor for RA formation through irreversible oxidation by RALDH [159]. However, [160] RALD is present in fat tissue where it may exert effects independent of its conversion to RA. RALD levels vary inversely with adiposity in mice fed a high fat diet while levels of ADH1 and RALDH1 are also differentially regulated. Mice lacking RALDH1 were protected against diet-induced obesity and diabetes. Consistent with the notion that RALD acts independent of its conversion to RA, administration of retinol, RALD, or RA to ob/ob mice had divergent effects on adiposity, with RALD limiting increases in visceral adiposity. Interestingly, in toxicology studies, citral, an inhibitor of RALDH activity, also induced weight loss. [161]. RALD appears to inhibit RXR:PPARγ activation. The implication of these findings for atherosclerosis remains to be determined. Another novel mechanism relating RA and fat metabolism is the recent observation that RA may have unique effects on lipid metabolism through differential effects on activating RARs versus PPARβ/δ [162]. RA is a proposed ligand for PPARβ/δ, a receptor involved in energy balance, lipid metabolism, and glucose homeostasis. PPARβ/δ activation increases lipid catabolism in skeletal muscle and adipose tissue, preventing the development of obesity [163]. Recent work suggests adipogenesis is accompanied by altered RA signaling in mature adipocytes, with activation of RARs and PPARβ/δ, thus enhancing lipolysis and depleting lipid storage. In diet-induced obesity, RA exposure induced the expression of RAR and PPARβ/δ target genes involved in regulating lipid homeostasis while fostering weight loss. More studies are needed to understand how retinoids and retinoid activated receptors modulate lipid metabolism and adipogenesis in the context of atherosclerosis. 13. Conclusion Atherosclerosis is a complex pathologic process that arises over decades, driven by diverse risk factors involving multiple cells and

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