Minireview: Won’t Get Fooled Again: The Nonmetabolic Roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the Heart

Abstract

The peroxisome proliferator-activated receptor (PPAR) transcription factors are nuclear receptors initially identified for their key role in regulating metabolic processes. Recent studies designed to identify the role of PPARα, -β, and -γ in vivo uncovered extrametabolic roles that may be less well known in the heart. In this review, we describe what is known about these extrametabolic roles of PPARs, including regulation of cardiac inflammation, extracellular matrix remodeling, oxidative stress, and regulation of cardiac hypertrophy. Lastly, we discuss the emerging role of PPARs in cell cycle regulation and angiogenesis in noncardiac systems that may be applicable to heart biology. Although this review primarily discusses the extrametabolic role of PPARα, the most studied PPAR isoform in the heart, we highlight where possible what is known about the unique and overlapping roles of the PPAR isoforms in terms of metabolic function.

We review PPAR’s extra-metabolic roles in regulating cardiac inflammation, extracellular matrix remodeling, oxidative stress, and cardiac hypertrophy in the context of their regulation of metabolism.

The healthy heart consumes more energy per gram of tissue than any other organ in the body and relies primarily on fatty acid catabolism to generate ATP (1). However, in physiological and pathological conditions, such as the postprandial state and in cardiac hypertrophy/heart failure, the heart is capable of switching substrate utilization toward glucose catabolism (2, 3). A family of transcription factors named the peroxisome proliferator-activated receptors (PPARs) regulates several of these metabolic adaptations (Fig. 1) (4). The predominant role of this family of transcription factors is the transcriptional regulation of enzymes and regulatory molecules involved in fatty acid and glucose metabolism; however, it is becoming more evident that there are additional PPAR-dependent pathways that are independent of the well-characterized metabolic functions of PPARs in the heart. In this review, we describe what is known about the extrametabolic roles of PPARs in the heart, including cardiac inflammation, extracellular matrix remodeling, oxidative stress, and regulation of cardiac hypertrophy. Lastly, we discuss the emerging role of PPARs in regulating the cardiac cell cycle and angiogenesis. To date, PPARα is the only isoform to be studied in each of these extrametabolic roles; therefore, we focus primarily on PPARα function and reference PPARβ and -γ studies when appropriate.

Fig. 1.

Regulation and mechanism of PPARα-mediated transcription. PPARα influences fuel metabolism through the transcriptional regulation of genes such as PDK4, FATP, FAT/CD36, CPT-1, and ACS (direct transcriptional targets, indicated by *) such that increases in PPARα activity favor fatty acids over glucose as the preferred fuel source of oxidative metabolism. Mechanistically, this model is applicable to all PPAR isoforms, regardless of ligand specificity and target genes, and consists of five distinct processes: 1) activation of PPARα and its binding partner retinoid X receptor (RXR) via ligand binding, usually a long-chain fatty acid, a fatty acid metabolite, or a synthetic ligand such as fenofibrate or WY-14643, and 9-cis retinoic acid, respectively; 2) nuclear translocation of the ligand-bound nuclear receptors; 3) heterodimerization of PPARα and RXRα and binding to the repeat response element in the promoter region of the target gene; 4) recruitment of coactivators, typically PGC-1α, promoting histone acetylation allowing RNA polymerase access to the DNA; and 5) gene transcription. Enhancing PDK4 activities through enhanced PPAR activation has a net inhibitor effect on the pyruvate dehydrogenase complex (PDC) through its kinase activity of the PDC. [Adapted from Stanley et al. (78 ); some graphical elements are courtesy of BioCarta.com.]. GLUT4, Glucose transporter 4; LCFA, long chain fatty acid; MCFA, medium chain fatty acid; PGC, PPAR coactivator; RA, retinoic acid; TCA, tricarboxylic acid cycle.

The Role of PPARs in Cardiac Inflammation

PPARα agonists inhibit the cardiovascular inflammatory response

There is a growing body of evidence demonstrating the effectiveness of PPAR agonists as antiinflammatory agents. For example, the PPARα agonist fenofibrate is a potent antiinflammatory drug used in the treatment of patients with rheumatoid arthritis (5). There is also evidence suggesting that PPAR agonists may also be useful in the fight against the cardiovascular inflammatory response. Patients with atherosclerosis who are treated with fenofibrate (a PPARα agonist prescribed to lower triglyceride/lipid levels) for 1 month, record a decrease in plasma levels of TNF-α, IL-1, and interferon-γ (6). Interestingly, the same decrease in inflammatory mediators is seen in healthy control patients, suggesting that PPARα activation attenuates inflammation both through its effect on lipid reduction, as well as through a novel PPARα-dependent mechanism. Atherosclerotic plaques, consisting mainly of macrophages and T cells, secrete TNF-α, IL-1, and IFN-γ in addition to releasing interferon-γ in response to increased low-density lipoprotein levels (6). Therefore, it is plausible that the antiinflammatory effects of fenofibrate may be occurring at the cellular level, to somehow decrease macrophage and T cell activation, thereby reducing atherosclerotic inflammation. Further evidence of the antiinflammatory effects associated with PPARα comes from studies involving human aortic smooth muscle cells. Treatment of human aortic smooth muscle cells with various PPARα agonists [gemfibrozil, fenofibrate, or WY-14643 (pirinixic acid, a PPAR activator, primarily PPARα)] inhibits IL-1-induced secretion of IL-6 and prostaglandin, as well as cycooxygenase-2 expression (7). Moreover, treating hyperlipidemic patients with fenofibrate results in decreased plasma levels of IL-6, fibrinogen, and C-reactive protein, implicating a role of PPARα agonists in inhibiting inflammation in many cell types, including smooth muscle cells in cardiovascular disease (7). These findings are particularly important given the role that aortic smooth muscle cells play in the formation of atherosclerotic plaques.

PPARα regulates systemic inflammation by inhibiting the transcriptional activity of nuclear factor-κB (NF-κB), c-Jun, and activator protein 1 (AP-1)

Aortas from mice lacking PPARα expression (PPARα −/−) exhibit exaggerated IL-6 production compared with wild-type aortas when challenged with a nonspecific inflammatory stimulus, such as lipopolysaccharide (LPS), suggesting that PPARα plays a role in regulating systemic inflammation (8). This theory is supported by studies demonstrating that the IL-1β-induced increase in IL-6 mRNA in aortic smooth muscle cells can be inhibited by the addition of a PPARα ligand—an effect that is absent in smooth muscle cells isolated from PPARα −/− mice (8). So then, how does PPARα influence IL-6-mediated inflammation? Several regulatory elements are present in the IL-6 promoter, and it turns out that some of these sites are targeted by PPARα in its activated form, resulting in the inhibition of IL-6 promoter activity (8). In particular, the AP-1 and NF-κB response elements (which are responsible for IL-1β induction of IL-6) are targets for PPARα-induced interference of transactivation through PPARα’s direct interaction with p65 and c-Jun as shown in Fig. 2. Originally, it was thought that PPARα might compete with c-Jun and p65 by binding to overlapping response elements. However, PPAR activation does not activate IL-6 promoter levels, indicating that it does not likely inhibit IL-6 by interfering with p65 binding of a functional PPAR response element (8). The interference between PPARα and c-Jun or p65 occurs in a promoter-independent manner; therefore competition for binding sites cannot be excluded (8). PPARα inhibits NF-κB by a DNA binding-independent induction of IκBα (9) and by inhibiting the formation of the p50-NFκB0-CCAAT enhancer binding protein-β complex (10). The reciprocal transrepression between PPARα and AP-1/NF-κB (8) parallels the transrepression that has been described for PPARγ and other nuclear receptors (11, 12). Nuclear receptor-mediated transrepression in general occurs by several mechanisms, including the induction of IκBα, competition of limiting pools of coactivators, and by promoting glucocorticoid receptors-p65 interactions that prevent interaction of p65 with other proteins (12). Other groups have demonstrated that the nuclear receptors can negatively impact the chromatin microarchitecture of a transrepression-sensitive target and prevent the signal-dependent clearance of nuclear receptor corepressor complexes and can be mediated by sumoylation [as recently reviewed (12, 13, 14)]. Taking these mechanisms into account then, the increased inflammatory response seen in the LPS-challenged PPARα −/− aortas may be a result of a lack of these inhibitory NF-κB pathways, leading to increased IL-6 promoter activity (8).

Fig. 2.

PPARα inhibits inflammation (induced by TNFα IL-1, and IL-6 in this example) by inhibiting the downstream p65 subunit of NF-κB and the c-Jun subunit of AP-1 from transactivating their downstream target genes. Adapted from Delerive et al. (8 ) and Devchand et al. (79 ); some graphical elements are courtesy of BioCarta.com. LTB4, Leukotriene B4.

Activation of PPARα or PPARγ inhibits cardiac release of TNF-α in vitro

In response to heart failure and other cardiovascular diseases, circulating levels and myocardial expression of TNF-α increase (15, 16, 17). This has serious implications for overall cardiac function because TNF-α exerts a negative inotropic effect on cardiac muscle cells (18, 19, 20, 21). Given the ability of PPARα to suppress IL-6-mediated inflammation in aortic smooth muscle cells (8), it seems reasonable to suggest that PPARα might also aid in the repression of inflammation induced by TNF-α expression. Indeed, pretreatment of neonatal cardiomyocytes with the PPARα agonist gemfibrozil or the PPARγ/PPARα agonist troglitazone significantly decreases LPS-stimulated TNF-α release as well as the induction of TNF-α mRNA (22, 23). EMSAs demonstrates the PPARα agonist WY-14643 and the PPARγ agonist rosiglitazone reduced LPS-induced NF-κB activation by antagonizing NF-κB DNA activation (22). In addition, both PPARβ and PPARγ agonists similarly inhibit cardiomyocyte inflammatory responses in culture (18, 23, 24). These studies indicate that PPAR activators may represent a promising avenue of treatment of cardiovascular disorders involving an inflammatory response, a topic that is explored further in the next section.

Activation of cardiac PPARα inhibits myocardial inflammation in vivo

Several published studies focus on the antiinflammatory effects of PPARα activation on myocardial inflammation in vivo. Myocardial inflammation after cardiac injury contributes to cardiac dysfunction by influencing myocyte survival (apoptosis) and defects in contractility and remodeling, mediated in part through increased NF-κB activity (reviewed in Ref. 25). In rats infused with the vasoconstrictor angiotensin II (AngII), fenofibrate treatment significantly reduces blood pressure in part by reducing NF-κB activity by 50% (26). Fenofibrate also completely normalizes AngII-induced increases in expression of cardiac cell adhesion molecules such as vascular cell adhesion molecule 1, platelet-endothelial cell adhesion molecule 1, and intracellular adhesion molecule 1, and reduces AngII-induced expression of TGF-β1, collagen deposition, and macrophage infiltration (26). Other studies identify a role for PPARα activation on redox-regulated transcription factors during the development of left ventricular hypertrophy and heart failure in Dahl salt-sensitive rats in that fenofibrate inhibits the development of a compensatory hypertensive hypertrophy (discussed in detail below) and attenuates systolic and diastolic cardiac dysfunction (27). In addition, fenofibrate improves left ventricular hypertrophy, an effect that is attributed to blocking the increase in DNA-binding activity of numerous transcription factors such as NF-κB, AP-1, early growth response protein-1, SP1, and Ets-1 in the heart (27). Fenofibrate inhibits the hypertension-induced increases in adhesion molecule expression (vascular cell adhesion molecule 1, intracellular adhesion molecule 1), cytokines (such as TGF-β), and osteopontin compared with hypertensive controls (27). Fenofibrate treatment also inhibits the hypertension-induced increase in C-reactive protein release and the infiltration of macrophages and T cells into the left ventricle (27). Despite these positive effects of PPARα agonists, reactivation of the PPARα has been shown to have negative effects on cardiac function in the development of cardiac hypertrophy (28). These findings demonstrate that PPARα activators such as fenofibrate may be useful in treating cardiac hypertrophy and heart failure through the prevention of activation of key inflammatory signaling pathways and redox-regulated transcription factors responsible for heart failure in the left ventricle.

Cardiac remodeling occurs during the development of cardiac hypertrophy and heart failure and involves proinflammatory signaling pathways, such as NF-κB. To understand how PPAR activation attenuates inflammatory signaling pathways in the heart, recent studies addressed the effect of PPARα and PPARβ on the NF-κB signaling pathway. Neonatal cardiomyocytes challenged with phenylephrine or TNF-α increase expression of inflammatory (i.e. NF-κB responsive-) and cardiac hypertrophic markers within 2 and 24–48 h, respectively (29). In these same cells, expression of PPARα (and PPARβ) in the presence of their respective ligands inhibits p65-dependent NF-κB activity measured by luciferase reporter assays (29). Likewise, adenoviral-mediated expression of either PPARα or PPARβ in neonatal cardiomyocytes attenuates α1-adrenergic-induced expression of hypertrophic markers, suggesting that cardiac hypertrophy and inflammation are closely related through their interactions with NF-κB (29). Finally, a critical role for cardiac PPARα expression in vivo is illustrated by studies using PPARα −/− mice undergoing pressure overload-induced cardiac hypertrophy using transverse aortic constriction (TAC) where these mice exhibit exaggerated cardiac hypertrophy, detailed in the following section (30).

Cardiac PPARα in pathological hypertrophy regulates extracellular matrix, inflammatory signaling pathways, and oxidative stress

TAC has been used as a surgical model for pathological cardiac hypertrophy to identify differences in gene expression in the left ventricle of PPARα −/− hearts compared with wild-type hearts using microarray analysis at baseline and after 28 days of TAC (31). From this analysis it can be seen that, compared with wild-type hearts, PPARα −/− hypertrophied hearts differentially express gene clusters related to the extracellular matrix, immune response/inflammatory signaling pathways, and oxidative stress (31). PPARα −/− mice also exhibit increased mRNA levels of fibrotic (collagen 1, matrix metalloproteinase 2) and inflammatory (IL-6, TNF-a, cyclooxygenase-2) markers after hypertrophy compared with wild-type controls (30). Whereas a number of studies cited above implicate a role for PPARα in either cardiac inflammation or hypertrophy in vitro, these last two studies implicate PPARα directly, for the first time, in the regulation of cardiac inflammation during the development of cardiac hypertrophy in vivo.

Further investigation of the relationship between cardiac fibrosis and the activity of PPARs in vivo has been reported using two rat models of cardiac hypertrophy. In the first model, silicone implants slowly release deoxycorticosterone acetate-salt to induce chronic hypertension, inducing concentric left ventricular hypertrophy, and rats are treated with either fenofibrate or rosiglitazone for 3 wk (32). These studies revealed that both fenofibrate and rosiglitazone prevent deoxycorticosterone acetate-salt-induced cardiac fibrosis (determined by Sirius red staining) (32). However, both agonists fail to prevent the development of cardiac hypertrophy as determined by echocardiography and atrial natriuretic factor mRNA levels (32). Likewise, in an AngII infusion model of hypertension, treatment with fenofibrate attenuates the induction of TGF-β1 expression and collagen deposition (26). These data compliment the in vivo studies using pressure overload-induced hypertrophy, which identified that the lack of PPARα expression results in exaggerated extracellular matrix remodeling by microarray analysis (30, 31).

PPARα and Oxidative Stress in the Heart

Lack of PPARα expression in the heart increases oxidative damage and impairs manganese superoxide dismutase activity

Gene expression analysis of pressure overload-induced hypertrophy in PPARα −/− mice demonstrates the enrichment of several gene clusters corresponding to oxidative stress (31). Other studies document the role of PPARα in oxidative stress regulation in the heart by characterizing the presence of oxidative damage and oxidative countermeasures such as catalase, glutathione peroxidase, and manganese and copper-zinc superoxide dismutases. PPARα −/− hearts exhibit a 2- to 3-fold increase in oxidative damage relative to wild-type hearts, measured by 3-nitrotyrosine and 4-hydroxy-2-nonenal protein adduct formation, respectively (33). Interestingly, the majority of the identifiable nitrated protein is myosin heavy chain, the major mechanical component of the sarcomere. Contributing to increased oxidative stress susceptibility, the expression and activity of the antioxidant manganese superoxide dismutase is decreased by 33% and 50% (respectively) in PPARα −/− compared with wild-type hearts; however, copper-zinc superoxide dismutase, catalase, or glutathione peroxidase do not differ under these conditions (33). Taken in sum, these findings indicate a role for PPARα in the regulation of antioxidant pathways that buffer the heart from oxidative stress. However, the decrease in cardiac function in PPARα −/− hearts confounds the issue when determining whether the changes in oxidative stress markers are primary or adaptive events. Further in vivo studies using PPARα agonists will undoubtedly help delineate the role of PPARα-mediated regulation of oxidative stress-regulatory pathways.

PPARα Agonists and Their Role in the Development of Cardiac Hypertrophy

Several cell- and rodent-based studies explore the issue of PPARα-dependent cardioprotection in more detail and attempt to define the function of PPARα in the context of cardiac hypertrophy. The protective effect of PPARα agonists on cardiac hypertrophy has long been established in cell-based cardiomyocyte studies. When neonatal cardiomyocytes are treated with endothelin-1 to induce cardiomyocyte hypertrophy, coadministration with either fenofibrate or WY-14643 inhibits the hypertrophic response, evidenced by the attenuation of cardiomyocyte surface area and decreased protein synthesis rates (34). Subsequent studies using this model of cardiomyocyte hypertrophy have identified that fenofibrate inhibits endothelin-induced Akt and glycogen synthase kinase-3-β phosphorylation, thereby inhibiting the development of cardiomyocyte hypertrophy (35). These critical upstream signaling pathways regulate several facets of cardiac hypertrophy (36), including the regulation of protein synthesis. Inhibiting prohypertrophic signaling by PPARα activation may also be due to the fenofibrate-induced physical interaction between PPARα and the prohypertrophic transcription factor NFAT (nuclear factor of activated T cells), preventing NFAT nuclear translocation (35, 37) similar to the mechanism depicted in Fig. 2. Therefore, on a molecular level, PPARα agonists affect critical components of hypertrophy signaling (Akt, glycogen synthase kinase-3-β, and NFAT) in part through promoting physical interactions between proteins and also by other yet to be elucidated mechanisms (Fig. 3).

Fig. 3.

PPARα agonists inhibit the transcription factors NF-κB, AP-1, GATA, and NFAT which mediate the induction of genes responsible for the development of inflammation and cardiac hypertrophy. [Adapted from Takano et al. (80 )].

Although cell-based systems allow some insight into the molecular underpinnings of PPARα agonists and hypertrophy, studies of rodent-based models have also contributed to our understanding of how PPARα agonists regulate signaling processes in pathological cardiac hypertrophy development. Administration of fenofibrate generally improves a number of parameters in the development of pathological cardiac hypertrophy, including cardiac function and reducing cardiac mass (27, 38, 39, 40, 41, 42). Specifically, fenofibrate inhibits hypertension-induced hypertrophy and attenuates the associated systolic and diastolic dysfunction, resulting in improved survival in Dahl salt-sensitive rats (27). Fenofibrate also decreased aldosterone-induced left ventricular hypertrophy in FVB mice and improved fractional shortening after 4 wk of fenofibrate treatment (40). However, fenofibrate treatment of PPARα −/− mice exacerbated left-ventricular dilation and decreased left ventricular function determined by fractional shortening, indicating that the PPARα-independent effects of fenofibrate worsen cardiac function (42). Other studies also indicate that PPARα agonists may negatively affect cardiac function. Enhancing PPARα activity with WY-14643 in an established pressure overload model of rat cardiac hypertrophy has been shown to reverse the down-regulation of measured PPARα-regulated genes in hypertrophied hearts (28). Enhancing PPARα activity in this study resulted in a severe depression of cardiac power and efficiency, maybe in part due to the prevention of the fatty acid-glucose substrate switch (28). Other studies suggest that stimulating PPARs may be detrimental to cardiac function as well. Dual PPARα/γ agonists have recently been developed to treat type 2 diabetics and simultaneously prevent the progression of cardiovascular complications. However, clinical development of these dual PPARα/γ agonists, such as muraglitazar and tesaglitazar, has been discontinued because of a higher incidence of edema and heart failure (43, 44, 45). However, improved atherogenic dyslipidemic profile was shown when the PPARα/PPARγ agonists fenofibrate and rosiglitazone were administered simultaneously (46). Although dual and pan-PPAR agonists are still being developed to treat diabetics with hyperlipidemia [PPAR α/γ, PPARα/β (47, 48, 49), PPARα/β/γ (50, 51)], the early failures of dual PPARα/PPARγ agonists bring to light the potential adverse cardiovascular events that could occur by stimulating PPAR isoforms in an unbalanced manner.

There is no consensus on which pathways are affected by PPARα agonists. For example, in spontaneously hypertensive rats, fenofibrate administration results in decreased expression of AP-1 and cFos/c-Jun heterodimers, leading to a decreased expression of their downstream target genes, such as collagen (38). Fenofibrate also inhibits the up-regulation of a cadre of redox-regulated transcription factors such as NF-κB and early growth response protein-1, normally induced by high-salt diets that promote cardiac hypertrophy (27). Other published studies demonstrate the efficacy of fenofibrate in preventing cardiac hypertrophy in a multitude of in vivo models including: high-fat/high-sucrose diet-induced (39), aldosterone-induced (40), partial abdominal aortic constriction-induced (41), and pressure overload-induced cardiac hypertrophy (42). Fenofibrate also has both PPARα-dependent and PPARα-independent effects in the development of cardiac hypertrophy in vivo which have been demonstrated using PPARα −/− mice (42). In wild-type mice, fenofibrate reduces cardiac inflammation, hypertrophy, and fibrosis (42). When PPARα −/− mice are treated with fenofibrate and challenged with cardiac hypertrophy, they experience an increased mortality, significant dilation, and decreased function determined by echocardiography (42). A more thorough analysis of all the potential mechanisms by which PPARα inhibits hypertrophy is needed to understand the common mechanisms through which PPARα attenuates the hypertrophic response in vivo. It is also important to understand the scenarios in which PPARα agonists may potentially be detrimental to cardiac function and outcomes.

Emerging Extrametabolic Roles of PPARα in Other Systems

In this review we have discussed how PPARs regulate a multitude of nonmetabolic signaling pathways in the heart, such as inflammation, extracellular matrix remodeling, antioxidant systems, and cardiac hypertrophy. Further evidence suggests that PPARs also play a role in regulating cell cycle and angiogenesis in noncardiac systems (Fig. 4). Because both regulation of the cell cycle and angiogenesis potentially impact the pathogenesis of ischemic heart disease and other cardiac pathologies (52, 53), understanding how PPARα regulates these processes may help understand the role of PPARα in diseases beyond cardiac hypertrophy.

Fig. 4.

Overview of the nonmetabolic biological processes regulated by PPARs discussed in this review. COX-2, Cyclooxygenase 2; GSK, glycogen synthase kinase; MMP, matrix metalloproteinase.

PPARα regulates proliferation and cell cycle

Activation of vascular smooth muscle proliferation plays a vital role in the development of atherosclerosis and in restenosis after endovascular surgery (54). In response to injury, smooth muscle cells migrate from the media to the intima, where they proliferate. This process involves the transition from quiescence to reinitiation of the G₁ cell cycle phase, resulting in actively dividing cells. Cell cycle progression is regulated by temporal regulation of several cyclin-dependent kinases and the resultant phosphorylation of various target proteins throughout each phase of the cell cycle. PPARα activation suppresses the cell cycle in vascular smooth muscle cells, inhibiting the G₁ to S phase transition by targeting the cyclin-dependent kinase inhibitor p16 (INK4a), also known as cyclin-dependent kinase inhibitor 2A (55) and can inhibit intimal hyperplasia (56). This inhibition may be quite beneficial in the setting of coronary atherosclerosis or after stent implantation.

Regulation of angiogenesis

Angiogenesis, defined as the formation of new blood vessels from preexisting vasculature, occurs during embryonic development and is necessary for wound healing, including cardiac ischemic insults (57), and is related to a host of pathophysiological conditions, such as diabetic retinopathy and cancer (58, 59, 60). The angiogenic process is tightly regulated by both pro- and antiangiogenic factors, predominantly signaling through the vascular endothelial growth factor (VEGF) pathway (61, 62). A number of pathological and physiological insults stimulate VEGF expression, including hypoxia and tumor genesis. VEGF signaling occurs mainly through interaction with its receptor VEGF receptor 2, which acts downstream to increase vascular endothelial permeability, proliferation, and migration (63, 64). Increased VEGF expression occurs in most tumors, suggesting its importance in supporting tumor growth. VEGF-neutralizing agents that inhibit tumor growth in vivo are in use clinically and recently reviewed (59, 60, 65, 66).

PPARα ligands inhibit cell proliferation and migration, inducing endothelial cell apoptosis, attributed in part to PPARα-dependent inhibition of VEGF receptor 2 expression in endothelial cells through binding the transcription factor Sp1 and preventing Sp1-mediated transactivation (67). Similarly, the PPARα agonists WY-14643 and LY-171883 interfere with the transcription factor AP-1 to inhibit PMA-mediated transcription of VEGF (68), a mechanism implicated in inhibiting cardiac hypertrophy. The antitumor effects of PPARα agonists may be explained by these antiangiogenic effects. Both fenofibrate and WY-14643 suppress VEGF secretion in glioblastoma cells and Lewis lung carcinoma cells, leading to inhibited angiogenesis and tumor growth (69). VEGF expression is also inhibited by the PPARα ligand clofibric acid in tumor xenografts and cancer cell lines, which exhibit decreases in angiogenesis, microvessel density, and tumor growth (70, 71). Therapeutic doses of fenofibrate reduce circulating VEGF levels (72) while reducing adventitial angiogenesis in a model of coronary angioplasty (53). These studies suggest increasing PPARα activity using fibrates could be detrimental in the face of ischemic heart disease by suppressing proangiogenic factors (e.g. VEGF). Enhancing PPARα activity may prove detrimental in the face of ischemic heart disease, where recovery depends in part on the ability to make collateral vessels. The role of PPARs in cardiac angiogenesis, however, has not yet been tested.

Conclusion

Myocardial remodeling during cardiac hypertrophy and heart failure involves the dynamic interplay between a host of signaling pathways. The role of PPARs in regulating cardiac metabolism is well established. During the development of cardiac hypertrophy and heart failure, PPAR expression levels decrease, leading to decreased fatty acid oxidation and parallel increases in glucose oxidation (3, 4, 73). However, this is just the beginning of how PPARs function in the heart. Several lines of evidence demonstrate PPAR activation exerts cardioprotective effects by inhibiting inflammatory responses through repression of the NF-κB-, c-Jun-, and AP-1-signaling pathways. The cardioprotective role of PPARα is further evidenced by increased oxidative stress, lower superoxide dismutase activity, and increased interstitial fibrosis in PPARα −/− mice. Emerging studies have identified a role for PPARα in cell cycle regulation/proliferation and angiogenesis, which are both essential cardioprotective processes in ischemic heart disease. Although this review focused largely on the role extrametabolic roles of PPARα due to the fact it is the most widely studied and most enriched isoform in the heart (74, 75), the other PPAR isoforms certainly play a role in cardiac disease. For example, increased PPARγ expression occurs in volume overload-induced heart failure (76) and restenosis after balloon injury (77). It may be the imbalance of PPARα and PPARγ expression that may contribute to cardiac disease and function through both metabolic and nonmetabolic pathways. The metabolic roles of PPARα, PPARβ, and PPARγ differ a great deal in animal models (4), and therefore it would not be surprising if each had unique and complimentary roles in extrametabolic processes yet to be discovered.

NURSA Molecule Pages:

• Ligands: Clofibrate | Fenofibrate | Pirinixic acid | Rosiglitazone | Troglitazone;

• Nuclear Receptors: PPARδ | PPAR-α | PPAR-γ.