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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:977.)
© 2006 American Heart Association, Inc.

Brief Reviews

Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR– Activators

Clinical and Experimental Evidence

Alberto Zambon; Philippe Gervois; Paolo Pauletto; Jean-Charles Fruchart; Bart Staels

From Institut Pasteur de Lille (P.G., J.-C.F., B.S.), Département d’Athérosclerose, Lille, France; Inserm (P.G., J.-C.F., B.S.), U.545, Lille, France; Université de Lille 2 (P.G., J.-C.F., B.S.), Lille, France; Department of Medical and Surgical Sciences (A.Z., P.P.), Clinica Medica 1, University of Padua, Padua, Italy.

Correspondence to Phillipe Gervois, Université de Lille 2, Pasteur Institute, 1 rue du Prof Calmette, Lille, 59019 France. E-mail philippe.gervois{at}univ-lille2.fr

	Abstract

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor (TNF)- and interleukin (IL)-6. Peroxisome proliferator-activated receptor (PPAR-)- is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR- is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR- agonists impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved, (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-, IL-1, and IL-6, leads to a decreased leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR- agonists may promote plaque stabilization and reduce cardiovascular events, via effects on metalloproteinases, such as MMP9. Moreover, PPAR- activation by fibrates also impairs proinflammatory cytokine-signaling pathways in the liver resulting in the modulation of the acute phase response reaction via mechanisms independent of changes in lipoprotein levels. Effective coronary artery disease (CAD) prevention requires the use of agents that act beyond low-density lipoprotein cholesterol-lowering. PPAR- agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Atherosclerosis is a long-term chronic inflammatory disease associated with increased concentrations of inflammatory hepatic markers, such as CRP and fibrinogen, and of peripheral origin, such as tumor necrosis factor- and interleukin-6. Peroxisome proliferator-activated receptor (PPAR-)- is a ligand-activated transcription factor that regulates expression of key genes involved in lipid homeostasis and modulates the inflammatory response both in the vascular wall and the liver. PPAR- is activated by natural ligands, such as fatty acids, as well as the lipid-lowering fibrates. PPAR- agonists appear to comprehensively address some of the abnormalities of the most common clinical phenotypes of the high CAD risk patient of the 21^st century such as in the metabolic syndrome and type 2 diabetes: low high-density lipoprotein cholesterol, high triglycerides, small, dense low-density lipoprotein, and a proinflammatory, procoagulant state.

Key Words: atherosclerosis • C-reactive protein • fibrates • inflammation • peroxisome proliferator-activated receptors

	Introduction

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the superfamily of nuclear receptors.¹ PPARs are activated by natural ligands such as fatty acids, eicosanoids, and oxidized fatty acids.^2–6 Of the 3 PPAR family members, PPAR-, PPAR-ß/ , and PPAR-, PPAR- is the target of the lipid-lowering fibrates.^3,7 PPARs regulate gene expression by forming heterodimers with the retinoid X receptor (RXR) and binding to specific DNA sequences located in the promoter region of target genes, termed PPAR response elements (PPRE transactivation). PPREs consists of a direct repeat (DR) of a hexameric AGGTCA recognition site separated by 1 (DR-1) or 2 nucleotides (DR-2).^8,9 A physiological role for PPAR- is to control FA oxidation in response to fasting by inducing ketone body formation^10,11 and high-fat–feeding.¹² PPAR- also plays a major role in lipid homeostasis by controlling key genes encoding enzymes and apolipoproteins involved in lipoprotein metabolism.¹³. Furthermore, PPAR- displays antiinflammatory activities and controls the inflammatory response in the vascular wall.^14–17 The control of inflammatory pathways by PPAR- occurs mainly via repression of target genes caused by negative interference in a DNA-binding–independent manner (transrepression)^14–17. It is well-established that serum concentrations of hepatic inflammatory response genes (eg, fibrinogen, C-reactive protein [CRP], serum amyloid A) are elevated in patients with coronary artery disease (CAD) and several of them, including fibrinogen and CRP, are considered as risk markers.^16,17 In this review, we focus on recent data demonstrating functions of PPAR- in hepatic inflammation and the clinical evidences of pleiotropic effects of PPAR- activators. We discuss the molecular mechanisms of PPAR- interference with several steps of the inflammatory cytokine signaling cascade in the hepatocyte.

	PPAR-: A Regulator of the Inflammatory Response

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Atherosclerosis is considered as an inflammatory disease.¹⁸ The vascular lesions of atherosclerosis are not only the result of lipid accumulation but also the result of vascular injury leading to activation of specific cellular and molecular responses that involve cells of the vascular wall and of the immune system. Modification of endothelial cell properties includes modified adhesion capacity of the endothelium surface that increases adhesion of circulating cells such as monocytes and lymphocytes. The endothelial dysfunction leads the endothelium to secrete cytokines and growth factors that in turn activate immune cells. If this inflammatory response is not efficient enough to block injury, inflammation becomes chronic and results in migration and proliferation of cells in the vascular wall initiating or exacerbating atherosclerosis processes. A role for PPAR- as a general modulator of the inflammatory response was provided by Devchand et al,⁴ who demonstrated that inflammation is prolonged in PPAR-–deficient mice. Subsequently, PPAR- was found to regulate the inflammatory response in vascular cells (Figure 1).^14,16,19 For example, PPAR- activation results in the inhibition of the production of endothelin-1, vascular cell adhesion molecule (VCAM)-1, IL-6, and tissue factor in endothelial cells, smooth muscle cells, and macrophages.^{6,14–16,20–22} In vivo evidence of an antiinflammatory action of PPAR- came with the demonstration that aortas from PPAR-–deficient mice display an exacerbated inflammatory response to lipopolysaccharide stimulation.¹⁵ Because PPAR- is highly expressed in the liver, a role for PPAR- as a modulator of the inflammatory response at the hepatic level, the acute phase response was thereafter demonstrated (Figure 1).¹⁷ The acute phase response is a generalized response of the organism to multiple disturbances of its physiological homeostasis, which is exacerbated under conditions of sepsis. Although inflammatory processes are important for the initiation of defense mechanisms,²³ they can become deleterious under situations of chronic activation. Produced as part of systemic inflammatory reactions, IL-6 and IL-1 induce acute phase protein (APP) genes in liver cells, such as CRP, fibrinogen, serum amyloid A (SAA), and 2-macroglobulin.^24–26 Elevated levels of IL-6 and liver APPs are found in patients with acute coronary syndrome and reflect the inflammatory state.^27,28 The expression levels of APPs are regulated by fibrates,^16,29,30 which act via a PPAR-–dependent mechanism.^31,32 Hence, several acute phase response markers such as fibrinogen, CRP, SAA, 2-macroglobulin, and plasminogen are lowered after fenofibrate treatment in humans, whereas levels of albumin, a negative acute phase response protein, are raised.

View larger version (20K): [in this window] [in a new window]   Figure 1. PPAR- is a modulator of the inflammatory response acting at the level of the vascular wall and the liver.

	Cellular and Molecular Mechanisms of the Hepatic Antiinflammatory Action of PPAR-

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Several studies have delineated the cellular and molecular mechanisms explaining the modulation of the hepatic inflammation response by PPAR- activation (Figure 2). Transcription of target genes by proinflammatory cytokines, such as tumor necrosis factor (TNF)-, IL-1, and IL-6 is mediated by several transcription factors acting alone or in combination. Among such transcription factors are CCAAT-enhancer binding proteins (C/EBP), signal transducer and activator of transcription proteins (STAT), the activator protein-1 (AP-1) complex including c-fos and c-jun, and the NF-B complex, which is most frequently composed of p50 and p65 proteins. Transcriptional activity is mediated by interaction with cofactors that remodel chromatin and bridge the DNA-bound transcription factors to the basal transcription machinery. Therefore, a decrease in cofactor availability would strongly affect transcription. This constitutes a first antiinflammatory mode of action of activated PPAR-. For instance, through the binding and titration of GRIP1/TIF2, a coactivator for C/EBPß, PPAR- interferes negatively with IL-6 transcription induction. This mechanism may participate in the inhibition of several C/EBPß/GRIP1-regulated APP genes by fibrates, including fibrinogen-, fibrinogen-ß, and serum amyloid A.³¹

View larger version (25K): [in this window] [in a new window]   Figure 2. Interaction of PPAR- at several levels of the inflammatory signaling pathway. Example of interference with the NF-KB pathway. PPRE, peroxisome proliferator response element; NF-KBRE, NF-KB response element. (1) Interference with activation of the transcription initiation complex via cofactor interaction. (2) Lowering of transcription factor expression levels. (3) Inhibition of nuclear translocation of inflammatory transcription factors. (4) Direct protein–protein interaction and induction of inhibitory protein expression such as IKB. (5) Downregulation of the expression of signal transducing receptor components.

Transcriptional activity of transcription factors moreover depends on its level of expression and its cofactors. This constitutes a second mechanism of modulation of inflammatory responsive genes by PPAR-. Such mechanism likely contributes to the inhibition of CRP promoter activity by PPAR- activators.³² PPAR- activators decrease expression levels of p50–NF-B and C/EBP-ß in the livers of wild-type mice, but not in PPAR-–deficient mice, as well as in human hepatocytes rendering the CRP promoter virtually unresponsive to IL-1. This type of mechanism may also participate in the modulation of the IL-6–induced acute phase response, which critically depends on the concentrations of C/EBPs present in the cell.^33–35 In addition to C/EBPß, hepatic expression of C/EBP and C/EBP is also lowered after chronic treatment of mice with fenofibrate.¹⁷

Cytokine-activated signal transduction pathways can also modulate the transition of inactive to active forms of transcription factors via altering their phosphorylation. Therefore, modulation of transcription factor phosphorylation status constitutes another level of control. For instance, phosphorylated c-Jun enhances IL-6-mediated activation of transcription.^36,37 Interestingly, whereas fenofibrate treatment only slightly reduced basal c-Jun levels in livers of wild-type mice, a strong reduction of phosphorylated c-Jun levels was observed in livers wild-type but not in PPAR-–deficient mice exposed to fenofibrate.¹⁷

Before reaching the nucleus, transcription factors reside in the cytoplasm as transcriptionally inactive complexes. Regulation of nuclear translocation constitutes a fourth mechanism for the modulation of transcription. PPAR- acts as a negative regulator of the inflammatory response through direct binding to p65–NF-B and c-Jun giving rise to inactive complexes^15,16 that antagonize the NF-B and AP-1 transcription factor pathways. NF-B localization is moreover tightly controlled by the levels of IB, which sequesters NF-B proteins in the cytoplasm. PPAR- activators also induce hepatic expression of IB, thereby preventing p50 and p65 translocation into the nucleus^32,38 (Figure 2). Thus, cytosolic retention of cytokine-stimulated transcription factors constitutes an additional mechanism of antiinflammatory properties of PPAR-.

Because interaction between PPAR- and NF-B leads to a modulation of the inflammatory response, a reciprocal effect of NF-B on PPAR- transactivation function and consequently on lipid metabolism is obviously expected. In vitro assays demonstrated that translocation of NF-B into the nucleus represses PPAR- transactivation of a PPRE-driven promoter. In addition, Morishima et al³⁹ reported that activation of NF-B signaling decreases apo A-I expression by blocking PPAR- transcriptional activity. Taking into account that PPAR- blocks inflammation stimulated SAA expression, physical interaction between PPAR- and NF-B constitutes a central cross-talk linking regulation of inflammation and lipid homeostasis at the gene level (Figure 3).

View larger version (19K): [in this window] [in a new window]   Figure 3. Hepatic control of HDL metabolism by PPAR-: a dual, cooperative mechanism of transactivation of apoA-I (+) and of transrepression of SAA(–). SAA, serum amyloid A; TF, transcription factor activated after cytokine stimulation, TFRE, response element-specific of TF.

The first event in activation of signaling is the binding of the cytokine to signal-transducing membrane receptor components. The responsiveness of a given cell type to cytokines is tightly tuned by the level of expression of their respective receptor components and represents a fifth crucial regulatory mechanism (Figure 2). Interestingly, IL-6 effects on acute phase gene expression are fully suppressed in fenofibrate-treated wild-type, but not in PPAR-–deficient, mice.¹⁷ The global effect of chronic PPAR- activation on the expression of positive and negative acute phase genes suggests the existence of an upstream suppression of the IL-6 pathway. IL-6 induces acute phase genes via a receptor system, consisting of the IL-6R/gp80 and gp130 proteins, which initiate a signaling cascade leading to downstream activation of transcription factors, such as C/EBPs and STATs. In fenofibrate-treated wild-type mice, PPAR- downregulates expression levels of the IL-6R gp80 and the signal transducer gp130 and, accordingly, reduces levels of phosphorylated STAT3.¹⁷ Reduced expression of membrane levels of cytokine-receptors may thus contribute to the global suppression of IL-6 induced acute phase gene transcription by PPAR- agonists. The action of PPAR- on acute phase gene expression is not restricted to the IL-6 signaling pathway. As shown in the case of CRP, chronic activation of PPAR- also prevents IL-1 stimulation of acute phase genes such as SAA by IL-1 in vivo (Gervois P, unpublished data, 2005).

PPAR- activation thus impairs cytokine-signaling pathways in the liver, acting at different levels, resulting in a potent modulation of the acute phase response reaction. In addition to its antiinflammatory action in the vascular wall, PPAR- plays a determinant role in the control of hepatic inflammation and as such dampens the expression of hepatic cardiovascular risk factors, such as CRP.

	Clinical Evidence of Pleiotropic Effects of PPAR- Agonists

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Atherosclerosis is a long-term chronic inflammatory disease¹⁸ characterized by the accumulation of lipids and fibrous connective tissue within the arterial wall.^18,40 The prevalence of a clustering of metabolic disorders, defined as the metabolic syndrome (MS),⁴¹ that includes insulin resistance, dyslipidemia, hypertension, central obesity, coagulation disorders, and increased plasma levels of markers of inflammation, such as CRP⁴² and fibrinogen, is taking epidemic proportions. Appropriate management of patients with the MS will be a major challenge for cardiovascular disease prevention in the next decades. The MS is highly prevalent (20% to 25%) among the adult population in North America and Europe,^43,44 and it is associated with a 3-fold increased risk for cardiovascular and cerebrovascular death.^45,46 PPAR- regulates lipid and lipoprotein metabolism and hemostasis, and, as outlined in the previous section, modulates the inflammatory response. Thus, PPAR- activators appear an interesting therapeutic option for the treatment of diseases related to atherosclerosis beyond their effects on lipid levels.

Clinical trials with PPAR- agonists either on CAD prevention, such as the Helsinki Heart Study⁴⁷ and VA-HIT⁴⁸ with gemfibrozil, or on coronary disease progression, such as the BECAIT trial⁴⁹ with bezafibrate, showed a significant reduction in cardiovascular events. Moreover, the LOCAT study with gemfibrozil⁵⁰ and the DAIS Study⁵¹ with fenofibrate showed a slower progression of coronary atherosclerosis compared with placebo-treated patients,^50,51 despite no or minor changes in total and low-density lipoprotein cholesterol (LDL-C) with treatment (ranging from 0% to –7%). The results of the VA-HIT are particularly interesting because the population was characterized by several features of the metabolic syndrome: low high-density lipoprotein cholesterol (HDL-C), slightly increased triglycerides with fairly normal LDL-C, overweight (mainly intra-abdominal obesity), insulin resistance (25% were diabetics), all features associated with LDL particles that are smaller, denser, and highly atherogenic as detailed in the following sections. A significant contribution to the role of PPAR- agonists on CAD prevention in patients with type 2 diabetes has became available very recently. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study,⁵² a combined primary and secondary prevention study, assessed the effects of treatment with fenofibrate in type 2 diabetic patients not eligible for lipid-lowering therapy at the start of the study. Significant and uncontrolled statin drop-in occurred during the course of the study, with a significantly larger number of patients in the placebo group receiving these hypolipidemic drugs at the end of the study. This statin drop-in, together with an 18% treatment drop-out, which was similar in both arms, likely influenced the primary end point (coronary heart disease death and nonfatal myocardial infarction), which was not significantly reduced by fenofibrate administration (–11% relative risk reduction). After normalization for statin drop-in, fenofibrate treatment was estimated to significantly reduce the primary end point by approx. 19%. In addition, significant beneficial effects were observed on total cardiovascular events (–11%), mainly caused by a significant decrease in coronary and overall revascularization procedures, and microvascular complications (reduced need for laser treatment for retinopathy: –30%; reduced progression of albuminuria). Fenofibrate therapy appeared to be specifically beneficial in reducing coronary heart disease events (–25%) in type 2 diabetics without previous cardiovascular disease. In addition, the FIELD study did not reveal any notable adverse events of fenofibrate in monotherapy or in combination with statins with the exception of a slight increase in deep vein thrombosis and pulmonary embolism, as well as pancreatitis. An important question still open after the FIELD study concerns the clinical efficacy of fibrate treatment in combination with statins. This will be investigated in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (http://www.accordtrial.org). The ACCORD study is a National Heart, Lung, and Blood Institute (NHLBI) sponsored study on 10 000 adults with type 2 diabetes to test the effects on major cardiovascular events of intensively controlling blood sugar along with aggressive control of blood pressure and lipids. Patients in the lipid-lowering arm will be randomized to receive either simvastatin (20 mg) alone or simvastatin plus fenofibrate. This study, with a follow-up of 4 to 8 years, will be available not earlier than 2010 and should provide definitive data as to the benefits of combination therapy with a statin plus a fibrate.

Involvement of PPAR- in modulating atherosclerosis processes has been evaluated in vivo in genetically modified mouse models but provided conflicting data. Most studies demonstrated a beneficial action of PPAR- agonists on atherosclerosis in rodents. For instance, fenofibrate ameliorates the lipid profile in dyslipidemic mice to a less atherogenic phenotype⁵³ and reduces atherosclerosis in apolipoprotein E (apoE)-deficient mice.⁵⁴ PPAR- activation was also found to strongly reduce atherosclerosis in LDL-receptor–deficient mice.⁵⁵ By contrast, Tordjman et al by studying the impact of PPAR- deficiency in atherosclerosis processes using the double knockout PPAR-/apoE mice model,⁵⁶ unexpectedly demonstrated that PPAR- null mice display less atherosclerosis. These observations indicate that whole body PPAR- deficiency does not result per se in opposed effects of ligand activation.

Cancer risk represents potential concern when considering the pharmaceutical use of novel highly active PPAR- agonists. PPAR- was identified as a major factor mediating peroxisome proliferation, hepatomegaly and hepatocarcinogenesis in response to peroxisome proliferators in rodent species.⁵⁷ Because new ligands for PPAR- are designed to display a high affinity for the receptor, it appears important to evaluate the carcinogenic response in pre-clinical models. However, many observations argue against a potential risk in humans. After 50 years of treatment with fibrates, no evidence for an action on cancer progression has been generated.^47,58,59 Moreover, PPAR-–humanized mice exhibit neither peroxisome proliferation nor hepatomegaly.⁶⁰ These data suggest that the carcinogenic effects of PPAR- agonists are restricted to rodent PPAR- and may be caused by differences in protein structure between human and rodent species.

The decrease in cardiovascular events and CAD progression in clinical trials with PPAR- agonists has been attributed to the triglyceride-lowering, HDL-C–raising actions of fibrates. However, these studies, supported by extensive evidence from in vitro and in vivo preclinical models, strongly suggest the presence of clinically relevant pleiotropic effects (ie, antiinflammatory, antithrombotic) of PPAR- agonists. The following paragraphs detail some of these atheroprotective effects in vivo and highlight a potential pathophysiological link with lipoprotein oxidation. Because this review focuses specifically on modulation of the inflammatory components of the atherothrombotic process by PPAR- agonists, the cardioprotective effects of PPAR- agonists related to blood pressure regulation and protection against cardiac ischemia will be only briefly discussed.

	PPAR- Agonists Influence Early Steps of the Atheroinflammatory Process: Monocyte Recruitment and Endothelial Function

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Adhesion of leukocytes to the vascular endothelium, and subsequent migration into the intima, are key events in the pathogenesis of atherosclerosis and are triggered by the expression of specific cellular adhesion molecules (CAM) on the endothelial cells.¹⁸ Induction of endothelial adhesion molecules, such as VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and E-selectin, is considered one of the earliest steps in atherogenesis. As previously discussed, in cultured human endothelial cells, PPAR- agonists significantly decrease VCAM-1 and ICAM-1 expression induced by inflammatory cytokines such as TNF-a, IL-1, and IL-6.¹⁴ These results have been supported by experimental evidence in patients selected over a broad range of HDL-C.⁶¹ In these patients, treatment with fenofibrate resulted in a significant decrease of circulating ICAM-1 and E-selectin levels. This effect is partly accounted for by the increased HDL-C levels after treatment with fenofibrate. However, in vivo evidence also supports a direct effect of fibrates on TNF-, IL-1, and IL-6–induced CAM expression by the endothelium as recently seen in a clinical setting, in which administration of fenofibrate in patients with dyslipidemia resulted in a significant decrease in plasma concentrations of IL-6¹⁶ and TNF-⁶² (Table 1). In addition, fibrates may decrease leukocyte recruitment into the arterial wall also by inhibiting CRP-mediated expression and secretion of chemokines, such as monocyte chemoattractant protein-1.^63,64

View this table: [in this window] [in a new window]   TABLE 1. Pleiotropic Effects of PPAR Agonists: In Vivo Evidence

Dysfunction of endothelial-dependent vascular reactivity precedes the development of atherosclerosis.⁶⁵ Lipid-lowering treatment with statins consistently improves abnormalities in endothelial function associated with hyperlipidemia.⁶⁶ Recent evidence indicates that also PPAR- agonists, such as ciprofibrate and fenofibrate, significantly improve vascular reactivity in patients with combined hyperlipidemia^67,68 and type 2 diabetes^69–72 (Table 1). Interestingly, changes in vascular wall reactivity and endothelial function did not correlate with changes of lipid profiles during therapy, but rather with measurements of oxidative stress⁶⁹ and CRP⁶⁷ levels, both markers of the inflammatory state.

Overall, these results indicate a role for PPAR- agonists in the regulation of endothelial function with consequences for penetration of inflammatory cells in the intima of the arterial wall.

	PPAR- Agonists, Plaque Stability, and Coagulation

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Unstable plaques are prone to rupture leading to thrombus formation and vessel wall occlusion. Modulation of monocyte/leukocyte recruitment is crucial for plaque stability: the hallmark of the unstable atherosclerotic plaque is an abundance of macrophages and other inflammatory cells, with scarce smooth muscle cells in the fibrous cap region.^73,74 Maintenance of a thick, stable fibrous cap requires a balance between extracellular matrix production and degradation. Metalloproteinases (matrix metalloproteinase [MMP]), specifically MMP-9, are secreted by inflammatory cells (ie, monocytes) within the atherosclerotic plaque and mediate extracellular matrix degradation. PPAR- agonists decrease gene transcription, secretion (in response to inflammatory cytokines) and enzymatic activity of MMP-9 by macrophages.⁷⁵ This effect on MMP-9 occurs indirectly via a nitric oxide (NO)-mediated mechanism.⁷⁶ Plaque rupture leads to thrombus formation and occurrence of acute cerebrovascular and cardiovascular events. Fibrates modulates other factors promoting thrombosis such plasminogen activator inhibitor type 1 (plasminogen activator inhibitor [PAI]-1). Elevated levels of PAI-1 are associated with an increased risk of acute coronary syndromes and myocardial infarction.⁷⁷ In cultured human endothelial cells, fenofibrate and gemfibrozil significantly decrease PAI-1 levels and may as such modulate the risk of thrombus formation.^77–79 In vivo evidence, however, is still controversial and further investigation is needed.

	PPAR- Agonists and Inflammatory Markers of CAD: Effects on CRP, Fibrinogen, and IL-6

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Acute phase proteins, such as fibrinogen and CRP, are established risk markers for cardiovascular disease.^28,80 PPAR- agonists, such as fibrates, attenuate the expression of inflammatory proteins of the acute phase in vivo, including fibrinogen, CRP, and IL-6. Ciprofibrate, fenofibrate and bezafibrate reduce in vivo levels of fibrinogen by up to 20%, in contrast to gemfibrozil, which may increase its level.^81,82 Fenofibrate appears particularly effective in reducing fibrinogen levels in different groups of patients characterized by mild hyperlipidemia both with¹⁶ and without CAD,⁸³ and by hypertriglyceridemia and CAD⁸⁴ (Table 1).

PPAR- activators are as effective as other classes of lipid-lowering drugs, ie, statins, in lowering CRP plasma levels in vivo. In patients with different forms of dyslipidemia and CAD, fibrates decrease baseline CRP levels by 20% to 50%^{16,67,85–89} (Table 2), and these changes are not correlated with changes in lipid or fibrinogen levels.^67,87 None of these studies report an association between the fibrate effects on triglyceride, HDL-C (as well as on LDL-C), and the decrease in CRP levels. We cannot rule out, however, that the effect of fibrates on LDL size, density and susceptibility to oxidation, might contribute to the observed reduction in plasma CRP levels. However, in vitro and in vivo data in transgenic CRP mice show a direct effect on modulation of CRP gene promoter activity by PPAR- activators.^32,90 Moreover, an indirect effect of the PPAR- activator fenofibrate on CRP and fibrinogen synthesis in the liver is also plausible, because fenofibrate concurrently reduces plasma levels of IL-6¹⁶ and TNF-,⁶² 2 cytokines inducing APP expression in the liver. Interestingly, in PPAR-–deficient mice, fenofibrate has no effects on IL-6 expression.^15,17 A recent study by Després et al,⁸⁸ in abdominally obese patients with MS, confirmed the efficacy of a different fibrate, gemfibrozil, on CRP levels (32%), but failed to show any effect on IL-6 and TNF- levels. The relative lipid-lowering potency of fibrates as well as their effects on some of the inflammatory proteins of the acute phase varies in clinical studies. Such differences may reflect the relative potencies of the fibrates on human PPAR- but equally their specificity for PPAR- versus other PPAR- subtypes.⁹¹ For example, in a cell-based transactivation assay, fenofibric acid is a significantly better PPAR- activator than bezafibrate or clofibric acid. By contrast, whereas clofibric acid and fenofibric acid are selective activators of PPAR- with >10 fold selectivity for PPAR-, bezafibrate activates all 3 PPAR subtypes with comparable efficacy.

View this table: [in this window] [in a new window]   TABLE 2. Effect of PPAR Agonists on hs-CRP Levels: In Vivo Evidence

Because atherogenic dyslipidemias are frequently characterized by a prothrombotic/proinflammatory state,⁴² and because both fibrinogen and CRP are recognized as major independent risk factors for CAD, CRP and fibrinogen-lowering are likely to be beneficial and highly relevant for prevention of acute thromboembolic complications of atherosclerosis. Finally, the most active PPAR- activators such as ciprofibrate and fenofibrate not only affect CRP and fibrinogen levels but also may attenuate platelet hyperaggregability in hypercholesterolemic subjects.⁹²

	PPAR- Agonists and Lipid Oxidation: A Link Between "Classic" and "Pleiotropic" Effects of Fibrates?

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Elevated LDL-C is a well-established risk factor for CAD. However, a high proportion of CAD patients have plasma LDL-C within the normal range.⁹³ Size and density of LDL particles, independently of LDL-C levels, significantly contribute to the atherogenicity of these lipoproteins: smaller denser LDLs are associated with a 3- to 6-fold increased risk of CAD,⁹⁴ and are a key component (with low HDL-C and hypertriglyceridemia) of the most common lipid phenotype found in patients with established CAD.⁹⁵ Small dense LDLs are strong predictors of CAD progression.⁹⁶ The increased atherogenicity of small dense LDL is mainly attributable to their high susceptibility to oxidation.⁹⁷ Oxidized LDLs (ox-LDL) accumulate into macrophages accelerating foam cell formation and have enhanced endothelial toxicity. PPAR- agonists significantly and consistently increase LDL size and reduce LDL density in dyslipidemic patients,^98–102 as also recently confirmed by Farnier et al in patients with mixed hyperlipidemia.⁸⁵ Recent observations suggest that reduction of apoCIII plays a significant role in PPAR- agonist modulated increase in LDL size and buoyancy.¹⁰⁰ It is therefore plausible to hypothesize an antiinflammatory antiatherogenic effect of PPAR- agonists implicating their effects on LDL oxidation.

Direct evidence of PPAR- modulation of LDL oxidation is limited mostly to preclinical studies using animal models, possibly because of the technical difficulties in properly assessing ox-LDL concentrations in patients. Induction of PPAR- expression is associated with a decrease in ox-LDL in atherosclerotic plaques in insulin-resistant mice.¹⁰³ Treatment with PPAR- agonists reduce susceptibility of LDL to oxidation and plasma levels of ox-LDL LDL and, synergistically with -tocopherol, protect lipoproteins from lipid peroxidation.¹⁰⁴ An increase in LDL size reduces their susceptibility to be oxidized and is significantly associated with low levels of CRP (Zambon A, unpublished data, 2005) and fibrinogen.¹⁰⁵ PPAR- agonists modulate the generation of free radicals in endothelial cells, and this mechanism may contribute to a decrease of ox-LDL formation.¹⁰⁶ The effect of fibrates on CRP and fibrinogen may therefore be explained by both a direct effect of PPAR- on CRP and fibrinogen production by the liver, and a decreased ox-LDL concentration caused by PPAR-–mediated changes in LDL size and density, which may concurrently contribute to the observed reduction of APP plasma levels.

	PPAR- Agonists and Cardioprotection Beyond Modulation of Atherothrombosis

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
PPAR- is expressed in cardiomyocytes and regulates gene expression of key proteins involved in myocardial lipid and energy metabolism. Currently, data in human, as well as animal, models suggest that a compromised PPAR- activity may significantly contribute to cardiac hypertrophy and overall cardiovascular remodeling¹⁰⁷ under conditions of pressure overload, suggesting a potential role in the transition from compensated heart hypertrophy to heart failure in hypertensive heart disease.¹⁰⁸ Furthermore, activation of PPAR- seems to protects the heart from ischemia/reperfusion myocardial injury.¹⁰⁹ This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. PPAR- activators are able to modulate, in animal models, endogenous production of endothelin-1, a potent vasoactive peptide; chronic PPAR- agonist treatment reduces endothelin-dependent¹¹⁰ as well as salt-dependent hypertension.¹¹¹ Surprisingly, cardiac-restricted overexpression of PPAR- mouse model exhibit signatures of diabetic cardiomyopathy including ventricular hypertrophy, expression of genes related to pathologic hypertrophy growth, and systolic ventricular dysfunction.¹¹² Although controversial, data obtained from distinct preclinical models with overexpression or deficiency of PPAR- cannot be opposed per se to effects of treatment with PPAR- activators. Recent data in humans suggest that treatment of hypertriglyceridemic patients with fenofibrate may decrease both systolic and diastolic blood pressure.¹¹³

	Conclusions and Future Perspectives

Top Abstract Introduction PPAR-{alpha}: A Regulator of... Cellular and Molecular... Clinical Evidence of Pleiotropic... PPAR-{alpha} Agonists Influence... PPAR-{alpha} Agonists, Plaque... PPAR-{alpha} Agonists and... PPAR-{alpha} Agonists and Lipid... PPAR-{alpha} Agonists and... Conclusions and Future... References

 
Fibrate PPAR- agonists modulate the inflammatory components of the atherosclerotic process via mechanisms independent of their action on plasma lipoprotein levels. Their effects impact on different steps of atherogenesis: (1) early markers of atherosclerosis, such as vascular wall reactivity, are improved; (2) however, reduced expression of adhesion molecules on the surface of endothelial cells, accompanied by decreased levels of inflammatory cytokines, such as TNF-, IL-1 and IL-6, leads to a decrease in leukocyte recruitment into the arterial wall; (3) in later stages of the atherosclerotic process, PPAR- agonist treatment may lead to plaque stabilization and reduction in cardiovascular events, via effects on markers such as MMP-9.

The in vivo antiinflammatory action of PPAR- agonists is clearly reflected by a significant decrease in plasma concentration of CRP, IL-6 and fibrinogen, acute phase proteins that are recognized CAD risk factors.

Effective CAD prevention requires the use of agents that go beyond LDL-C lowering, addressing the abnormalities of the most common clinical phenotype of the high CAD risk patient of the 21^st century: low HDL-C, high triglycerides, small dense LDL, and a proinflammatory procoagulant state (such as in MS and in type 2 diabetes). PPAR- agonists currently available are beginning to meet these goals and, like the statins, appear to have numerous additional antiinflammatory and antiatherosclerotic actions in the arterial wall, making this class of drugs a crucial component in our therapeutic arsenal for cardiovascular disease prevention.

The observations that the different PPAR subtypes display distinct metabolic and pleiotropic effects gave rise to the development of compounds with dual activity on the PPAR- and PPAR-g receptors. The idea of "1 ligand for 2 receptors" is expected to provide a new therapeutic approach via complementary metabolic actions. This new class of combined PPAR-/ agonists should integrate the properties of thiazolidinediones (PPAR- agonists regulating insulin resistance and blood glucose levels) and fibrates (regulating lipoprotein metabolism). They hold considerable promise for improving the management of type 2 diabetes and provide a potential therapeutic option for the treatment of the multifactorial components of CAD and the metabolic syndrome, including inflammation control. Another emerging concept is based on selective PPAR activation by specific PPAR agonists. Such compounds should modulate selectively specific subsets of PPAR target genes and as such, result in more specific metabolic actions devoid of significant side effects. This selective PPAR modulator or "SPPAR-M" concept as well as the dual agonist concept represent attractive areas for future development of compounds with a diversity of potent clinical applications.

	Footnotes

 
A.Z. and P.G. contributed equally to the work.

Received August 5, 2005; accepted January 4, 2006.

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