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(Hypertension. 2004;43:297.)
© 2004 American Heart Association, Inc.

Corcoran Lecture

Peroxisome Proliferator-Activated Receptor : Implications for Cardiovascular Disease

From Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles.

Correspondence to Willa A. Hsueh, Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles Warren Hall, Suite 24–130, 900 Veteran Avenue, Los Angeles, CA 90095. E-mail whsueh{at}mednet.ucla.edu

Abstract

Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR is expressed by macrophages, endothelial cells, and vascular smooth muscle cells. It regulates gene expression of key proteins involved in lipid metabolism, vascular inflammation, and proliferation contributing to atherogenesis and postangioplasty restenosis. The discovery of synthetic ligands for PPAR has led to significant enhancement of our understanding of the mechanism of their ligand-dependent activation and subsequent biological effects, particularly with respect to the role of PPAR in vascular pathophysiology. The thiazolidinedione PPAR agonists not only improve insulin resistance in patients with type II diabetes but also exert a broad spectrum of antiatherogenic effects in vitro and in animal models of atherosclerosis. In this review, we summarize the important role of PPAR as a molecular target for thiazolidinediones and its implications for the control of vascular inflammation and proliferation for the cardiovascular system.

Key Words: atherosclerosis • diabetes mellitus • peroxisome proliferator-activated receptor • angiotensin • inflammation

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They have multiple metabolic and increasingly recognized cardiovascular effects.^1–3 PPARs regulate transcription of target genes by heterodimerizing with the retinoid X receptor (RXR) and binding to PPAR response elements (PPRE) of regulatory promoter regions of target genes.^4,5 On ligand-binding, a conformational change in the heterodimeric unit occurs such that corepressors are replaced by coactivators and gene transcription occurs.^6,7 Various ligands induce different conformations of the unit, recruiting different coactivators and resulting in different actions of the receptor.⁸ Thus, ligands can be developed that modulate the receptor, such as has been extensively described for the estrogen receptor.^9,10 Ligands for two forms of the receptor, PPAR and PPAR, are clinically available; ligands for PPAR are currently under development. Rosiglitazone and pioglitazone, both PPAR ligands of the thiazolidinedione (TZD) class, enhance insulin-mediated glucose uptake and are widely used for treatment of type 2 diabetes.¹¹ Fibrates are weak activators of PPAR, which regulate lipid and apolipoprotein metabolism to lower circulating triglycerides and increase high-density lipoprotein cholesterol (HDLC) levels.¹² Activation of PPAR appears to markedly enhance fat metabolism, which attenuates weight gain; to decrease triglycerides and increase HDLC, perhaps more potentially than fibrates; and to promote insulin sensitization.¹³ TZDs have little effect on PPAR, while fibrates do not activate PPAR, and neither activates PPAR. Future ligands on the clinical horizon, "balanced ligands," are being developed to activate PPAR and PPAR. A single ligand that activates all PPAR receptors is also being tested. Because all PPARs partner with RXR, a single ligand to RXR may also activate all PPARs; this strategy is also under development.

All three PPARs are expressed on vascular tissue.^14–18 The availability of PPAR and PPAR ligands has allowed much investigation of their vascular actions. In general, activation of both receptors inhibits atherosclerosis, although multiple mechanisms are involved (Table 1). Because of actions to improve insulin sensitivity, our laboratory has focused on PPAR. Ligands to PPAR have contributed substantially to our understanding of vascular injury in the setting of insulin resistance. Insulin resistance has clearly been shown to be associated with increased coronary artery disease (CAD), even well before its end stage, type 2 diabetes, which is now defined as an atherosclerosis risk equivalent.^19–21 This review focuses on the vascular protective effects of PPAR.

PPAR Ligands Consistently Attenuate Atherosclerosis

The administration of PPAR ligands consistently decreases atherosclerotic lesion formation in genetically prone mouse models: the low-density lipoprotein cholesterol receptor knockout (LDLR^-/-) and the apolipoprotein E knockout (APOE^-/-) (Table 2). This attenuation occurs independent of changes in circulating lipids, blood pressure, glucose, or insulin, implicating direct vascular actions. The effect occurs in insulin-sensitive or insulin-resistant models with or without diabetes, and thus appears generally independent of insulin resistance or diabetes.^22–25 Despite the presence of diabetes, the vascular lesions in all of these models are early fatty streaks. Advanced lesions, organized plaques with necrotic lipid cores covered by fibrous caps and surrounded by proteoglycan matrix, are more likely to occur in humans with diabetes, who have a marked increase in cardiovascular event rates compared with individuals without diabetes.²⁶ Compared with lesions from the latter, lesions of diabetic subjects are characterized by increased inflammation and oxidation and increased expression of the prothrombotic profibrotic substance, plasminogen activator inhibitor 1 (PAI-1), and the proinflammatory cytokine and adhesion molecule, osteopontin (OPN).^27,28 We sought to investigate a mouse model with lesions that resembled those in diabetes.

View this table: [in this window] [in a new window]   TABLE 2. PPAR Ligands Limit Atherosclerosis in Animal Models

Long-term infusion of angiotensin II (Ang II) in pressor or subpressor doses is associated with a marked acceleration of atherosclerosis.^29–31 Lesions become fibrofatty with occasional necrotic lipid cores, and a greater percentage of the aorta is covered by lesions (Wakino et al, unpublished observations, 2003). Ang II is a potent stimulus to vascular expression of PAI-1 and OPN, as well as inflammation and oxidation (Figure 2). ^28,32–34 We investigated the role of OPN in the APOE^-/- mouse infused with Ang II by breeding APOE^-/- with OPN^-/- to develop a mouse null for APOE and OPN, APOE^-/-/OPN^-/-35. Lack of OPN reduced atherosclerotic lesion formation by 65%, which was associated with decreased accumulation of macrophages in the vessel wall, despite a robust increase in monocyte chemoattractant protein-1 (MCP-1; Figure 1). OPN is expressed in all vascular tissues, vascular smooth muscle cells (VCMCs), endothelial cells (ECs), and macrophages.³⁶ To determine whether OPN loss from the vessel wall or macrophages contributed to our observations, we irradiated APOE^-/- and transplanted them with OPN^+/+ or OPN^-/- bone marrow. Animals receiving OPN^+/+ marrow had the same degree of atherosclerosis as APOE^-/- without irradiation, whereas those receiving OPN^-/- bone marrow had 70% attenuation of lesion formation suggesting OPN in the bone marrow was responsible for atherosclerosis development. We also examined a nonaccelerated form of atherosclerosis in 8-month-old APOE^-/-/OPN^-/- and their wild-type littermates, APOE^-/-/OPN^+/+ receiving a normal chow diet, which is relatively low in cholesterol. In male animals, we observed no difference in lesion extent in APOE^-/-/OPN^-/- compared with APOE^-/-/OPN^+/+, suggesting macrophage OPN is an important mediator of Ang II-accelerated atherosclerosis. OPN mediates multiple effects in macrophages, because lack of OPN is associated with decreased leukocyte migration, increased apoptosis, and increased interleukin (IL)-10 production, which inhibits monocyte adhesion and atherosclerosis development.^35–39 These results define macrophage OPN as an important mediator of the accelerated atherosclerotic process by promoting macrophage recruitment into injured vascular tissue. Indeed, these observations underscore the role of the macrophage in atherosclerosis, because knockout of MCP1 or its receptor CCR-2 also attenuates atherosclerosis in murine models,^40,41 and knockout of macrophage colony-stimulation factor (MCSF), which converts monocytes to macrophages, similarly attenuates atherosclerosis.⁴² Increased expression of OPN in lesions may suggest acceleration and has implications for CAD in the setting of diabetes and insulin resistance.

View larger version (18K): [in this window] [in a new window]   Figure 2. PPAR ligands inhibit multiple direct proatherogenic effects of angiotensin II.

View larger version (28K): [in this window] [in a new window]   Figure 1. Genetic deficiency in OPN results in marked reduction of angiotensin II-accelerated atherosclerosis in apoE-deficient mice. A, Atherosclerotic lesions of the thoracic aorta stained with Sudan IV from apoE-/-OPN+/+, apoE-/-OPN+/-, and apoE-/-OPN-/- mice 4 weeks after infusion with angiotensin II. B, Quantification of the atherosclerotic lesion area determined by computer-assisted image analysis. Data are represented as average percentage of the total surface of the thoracic aorta and expressed as mean±SEM. *P<0.05 versus ApoE-/-OPN+/+ infused with angiotensin II.

In the Ang II-accelerated atherosclerosis model we found that PPAR ligands consistently attenuated atherosclerosis.⁴³ The complement of ligands tested in the Ang II-infused LDLR^-/- mouse on high-fat diet included rosiglitazone, pioglitazone, and a non-TZD full PPAR agonist.⁴³ These PPAR ligands did not decrease Ang II-induced hypertension and only modestly altered glucose, insulin, or lipids, which suggests that they had direct vascular effects to antagonize the actions of Ang II. In addition, the repertoire of ligands tested had variable effects to improve insulin sensitivity, which is generally related to their transcriptional activity as measured by activation of PPRE–luciferace construct transfected into cells treated with the ligand.^11,44 Thus, the direct vascular effects appear to occur independently of the insulin-sensitizing effects. Whether these actions are unrelated because different coactivator/corepressor recruitment is required for these different functions, or whether there are different endogenous PPAR ligands in these different tissues remain to be determined. One likely mechanism that PPAR ligands inhibit atherosclerosis is through their anti-inflammatory properties.

PPAR Ligands Are Anti-Inflammatory

PPAR ligands inhibit a variety of inflammatory actions in macrophage including expression of inducible nitric oxide synthase (iNOS), superoxide dismutase, gelatinases, matrix-metalloproteinases, and several interleukins.^45,46 Some anti-inflammatory effects required high doses of ligand (50 µmol/L) in vitro and may occur independent of the receptor, suggesting that these may be "nongenomic" effects.⁴⁷ Most of these actions occur by inhibition of AP-1 and nuclear factor, B (NFB) signaling pathways, which transcriptionally regulate inflammatory genes.^48,49 In contrast, OPN is suppressed by an order of magnitude less PPAR ligand concentration and does not involve a NFB site but may involve AP-1.^50,51 In addition, we and others have observed that vessels from atherosclerotic-prone animals treated with PPAR ligands have less accumulation of macrophages, measured by CD68 expression, and less expression of MCP-1, vascular cell adhesion molecule-1 (VCAM-1), and tumor necrosis factor alpha (TNF) compared with vessels from untreated animals.^22,43 This observation is consistent with its action to suppress expression of these genes in cultured VSMCs and ECs.⁵²

Increasing evidence identifies adipose tissue as a major source of circulating inflammatory factors, particularly in the presence of obesity.⁵³ Fat produces proinflammatory adipocytokines, which include TNF, leptin, PAI-1, IL-6, and angiotensinogen.⁵³ TNF is a major activator of NFB.⁵⁴ TNF also inhibits insulin signaling, thereby causing insulin resistance.^55,56 Leptin activates the immune system and increases blood pressure; circulating levels correlate with CAD events in human studies.^57–59 PAI-1 levels predict CAD and diabetes, and they are a major contributor to the prothrombotic state in obesity.^60,61 IL-6 stimulates liver production of c-reactive protein (CRP) and contributes to the elevated highly sensitive (hs)CRP levels in serum of obese subjects.^62,63 HsCRP predicts myocardial infarction, stroke, peripheral arterial disease, and sudden death.^64–68 Angiotensinogen is the precursor of Ang II, which is well-known to activate multiple mechanisms of vascular injury, as discussed.³⁴ In general, all of these adipokines are elevated in insulin-resistant subjects with increased visceral adiposity creating a proinflammatory milieu. Weight loss is associated with decreased circulating levels of these cytokines, suggesting fat is a major source.^69,70 In contrast to these adipocytokines, adiponectin, also produced by fat, circulates in low levels in obese subjects and improve insulin-mediated glucose uptake and inhibit TNF activation of NFB.^71,72 It acts through two recently cloned receptors, AdipoR₁ and AdipoR_2, which are expressed in liver, skeletal muscle, vascular tissue, heart, and kidney.⁷³ When administered to ob/ob mice, adiponectin prevents diabetes, and in APOE^-/- mice it attenuates atherosclerosis.^74,75 Adipose tissue expresses the highest levels of PPAR compared with other tissues.⁷⁶ In the Zucker diabetic rate, TZD administration altered expression of 10% of the genes in adipose tissue, suggesting a major impact on the fat cell.⁷⁷ PPAR ligands promote fat cell differentiation and uptake of free fatty acids into adipose tissue.⁷⁸ They also have an important effect to attenuate the proinflammatory milieu by decreasing expression of TNF, PAI-1, and IL-6 and increasing adiponectin expression in fat.^45,46,79 In insulin-resistant, nondiabetic Mexican Americans, rosiglitazone administration decreased circulating levels of PAI-1 and hsCRP and increased adiponectin (W. Hsueh and M. Quiñones, unpublished observations, 2003). These observations are consistent with that reported for Japanese diabetic subjects and women with polycystic ovarian syndrome.^80–82 Thus, PPAR ligands suppress inflammation directly in vascular cells and indirectly through regulation of gene expression in adipose tissue.

PPAR Ligands Inhibit Cell Growth and Movement

Despite extensive investigation, the exact role of VSMC in the development of atherosclerosis remains unclear. The fibrous cap covering the necrotic lipid core of an organized atherosclerotic plaque is thought to result from movement and growth of VSMC into the area related to formation of the neointima.⁸³ There is also evidence suggesting that when the endothelium is damaged and neointima is formed by VSMC, atherosclerotic plaques develop in these area.^84,85 However, when more extensive damage of the endothelium occurs after angioplasty or stent placement, neointima formation leads to restenosis.⁸⁶ We identified that PPAR ligands inhibit growth and migration of VSMC and translated the effects in vivo to demonstrate that troglitazone inhibited neointima formation in rat aortae that had been injured by balloon catheterization.^14,87,88 These observations were confirmed in subjects with diabetes receiving coronary artery stent insertion.^89,90 The mitogen-activated protein kinase (MAPK) pathway has long been known to be involved in cell growth and more recently has been identified as a regulator of cell movement.^91–94 PPAR ligands appear to be involved in some aspects of activation of the MAPK pathway.^88,95–97 MAPK activates myosin light-chain kinase (MLCK), which is required for cell chemotaxis.⁹⁸ PPAR ligands do not inhibit phosphorylation of MLCK.⁹⁷ We found that these ligands act downstream of the cytosolic MAPK pathway and inhibit ets-1 expression, which regulates VSMC matrix-metalloproteinase (MMP) expression; MMP activity is required for cell movement.⁹⁷ Ligand-induced activation of PPAR also inhibits VSMC G₁-S phase progression of the cell cycle to prevent cell growth.^88,99 G₁-S progression involves association of cyclins with cyclin-dependent kinases (CDKs), which in turn are negatively regulated by cyclin-dependent kinase inhibitors (CDKIs).¹⁰⁰ Growth factors induce the expression of cyclins and the formation of cyclin-CDK complexes, and regulate CDKI levels by enhancing their degradation and ubiquitylation.^101,102 The mechanism by which PPAR ligands prevent human coronary artery VSMC growth involves the prevention of growth factor-induced degradation of the CDKI, p27, thus preventing formation of cyclin–CDK complexes and, ultimately, phosphorylation of the retinoblastoma (Rb) gene product.⁸⁸ Rb phosphorylation functions as a key switch, dedicating the cell into S phase of the cell cycle and mitosis.¹⁰³ Upon Rb phosphorylation, E2F is released and induces the expression of several genes involved in DNA replication including minichromosome maintenance proteins.^104,105 PPAR is directly involved in this regulatory process by inhibiting E2F transcriptional activation and the resulting expression of minichromosome maintenance proteins, which are necessary for the formation of prereplication complexes on DNA origins.⁹⁹

PPAR ligands also inhibit EC growth and movement, and thus are anti-angiogenic^106–109 The need for angiogenesis in atherosclerosis has been controversial. When vessels are completely thrombosed and occluded, new vessel formation provides continued blood flow to hypoxic tissues. However, small vessels grow inside atherosclerotic plaques and allow plaques to reach sizes greater than 250 µm.¹¹⁰ Inhibitors of angiogenesis inhibit plaque growth, and thus prevent formation of large plaques.¹¹¹ Whether PPAR ligands can impact on these processes remains to be investigated. We investigated the antiangiogenic potential of PPAR ligands in another context—diabetic retinopathy.^112,113 Oxygen-induced retinopathy and choroidal neovascularization by experimental laser photocoagulation resemble proliferative diabetic retinopathy. Both models are associated with a marked increase in retinal levels of vascular endothelial growth factor (VEGF), which promotes growth and chemotaxis of EC to form new vessels, but the vessels are leaky and unstable.^112,113 In diabetes, this neovascularization and leakiness leads to retinal hemorrhages and exudates, contributing to blindness. Intraocular injection of rosiglitazone or troglitazone into hypoxic mice prevented retinal neovascularization.¹¹³ This effect was not associated with a decrease in retinal VEGF levels, but PPAR ligands inhibited the effects of VEGF to promote migration and growth of cultured EC, which was also mediated by the MAPK pathway.¹¹³

PPAR Ligands and Reverse Cholesterol Transport

Ligand-induced activation of PPAR has been reported to regulate cholesterol efflux from macrophages through an induction of another nuclear receptor, liver X receptor (LXR), which is a critical regulator of the ATP-binding cassette protein-1 (ABCA-1).^114,115 This transport protein escorts cholesterol out of macrophages into HDLC, thus removing cholesterol from vascular and other tissues.¹¹⁶ This process of reverse cholesterol transport is important for atherosclerosis, because humans with defects in ABCA-1, Tangiers disease, have excess tissue cholesterol deposition, low HDLC, and increased CAD events and mortality.^117,118 Tontonoz and colleagues¹¹⁹ working with our team demonstrated that LXR agonists attenuate atherosclerosis; however, the same group also recently demonstrated that LXR ligands exert multiple vascular anti-inflammatory effects.¹²⁰ Thus, the antiatherosclerotic effect of LXR may be mediated by inhibiting inflammation, as well as reverse cholesterol transport.

PPAR Effect on Blood Pressure

Early studies revealed that pioglitazone lowered blood pressure in normotensive rats by inhibiting L-type calcium channels, although these effects occurred with relatively high ligand doses.^121,122 Clinically, troglitazone lowered blood pressure in subjects with impaired glucose tolerance.¹²³ Rosiglitazone and pioglitazone were also demonstrated to lower blood pressure in humans.^124,125 However, in our Ang II-infused mouse models, we use observed no effect of the ligands to attenuate blood pressure over a 2-month period.⁴³ More recently, rosiglitazone was observed to partially decrease blood pressure in the deoxycorticosterone acetate–salt hypertensive rat, whereas the PPAR ligand fenofibrate had no effect, although the PPAR and the PPAR ligands decreased vascular expression of endothelin-1 (ET-1).^126,127 Rosiglitazone and pioglitazone were also shown to attenuate blood pressure in the Ang II-infused rat, prevent vascular structural changes, and endothelial dysfunction in that model.¹⁰⁷ One mechanism may relate to reports that PPAR ligands decreased vascular expression of the Ang II AT-1 receptors^128,129. Whether these inconsistencies relate to rats versus mice and whether this mechanism plays a role in humans remains to be determined.

Evidence that PPAR Ligands Have Antiatherosclerotic Effects in Humans

PPAR ligand administration generally improves endothelial function in insulin-resistant, nondiabetic subjects and in patients with diabetes. Troglitazone improved brachial artery reactivity in diabetes, femoral artery reactivity in women with polycystic ovary syndrome, and microvascular responses in subjects with diabetes.^130,131 We recently demonstrated that troglitazone and rosiglitazone improved coronary artery endothelium-dependent blood flow measured noninvasively by positron emission tomography scanning in insulin-resistant subjects without diabetes or impaired glucose tolerance, smoking, hypertension, or hypercholesterolemia.¹³² This improvement was not related to changes in blood pressure, lipids, glucose, or hsCRP, but did correlate with the decrease in fasting insulin and in circulating PAI-1.¹³² Carotid IMT is an accepted biomarker of coronary events and changes in carotid IMT parallel coronary artery progression or regression.¹³³ Xiang et al followed-up subjects at high risk for diabetes on troglitazone for up to 4 years and found attenuation of atherosclerosis progression compared with a similar group of subjects receiving placebo.¹³⁴ Shorter studies of 3 to 6 months also suggested that TZD induce carotid IMT regression.^135,136

Conclusions

Currently, much animal and human data suggest that PPAR ligands will be vasculo-protective. Two clinical trials in patients with diabetes, one with rosiglitazone and the other with pioglitazone, are underway with primary endpoints of CAD events and mortality; and both are being tested to prevent diabetes. Thus, we have come a long way since our initial observation that troglitazone has direct vascular effects. PPAR ligands have substantially extended our understanding of the relationships between insulin resistance, inflammation, and atherosclerosis and may help curb the growing worldwide epidemic of insulin resistance.

Perspectives
If PPAR ligands successfully decrease atherosclerosis events and the incidence of type 2 diabetes, prevention strategies will drastically change for millions of obese individuals at risk with insulin resistance. Current approaches include lifestyle modification with emphasis on diet and exercise. Administration of metformin in individuals at high risk for diabetes who are younger than age 60 years or who have polycystic ovary syndrome delays the onset of diabetes, but effects on cardiovascular disease are not known.¹³⁷ In contrast, in the Tripod Study, troglitazone appeared to have longer-term effects to prevent diabetes once the drug was discontinued, and it delayed the progression of carotid IMT in the same cohort.¹³⁴ Despite these potentially exciting actions, we are just beginning to understand how PPAR ligand improve insulin action, and much less is known about how they may protect the vasculature. Elucidation of these mechanisms holds much promise in unraveling complex pathophysiologic alterations that relate insulin resistance and metabolic alterations to tissue injury, particularly in islet cells leading to diabetes and in blood vessels leading to atherosclerosis. Furthermore, our ability to perform structure function studies, rapidly screen candidate ligands, and evaluate drug actions via gene array analysis will allow us to develop powerful, targeted PPAR ligands with little side effects that can be administered to the large population of individuals at high risk. This approach is emerging as a major strategy to convert two important diseases of the Western world—diabetes and cardiovascular disease.

Received September 30, 2003; first decision November 3, 2003; accepted December 9, 2003.

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