Reviews |
From the Department of Internal Medicine IICardiology (N.M.), University of Ulm, Germany, and UR545 INSERM (H.D., J.-C.F., B.S.), Départment dAthérosclérose, Institut Pasteur de Lille, Université de Lille, France.
Correspondence to Nikolaus Marx, MD, Department of Internal Medicine IICardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-mail nikolaus.marx{at}medizin.uni-ulm.de
This Review is part of a thematic series on Nuclear Receptor Signaling, which includes the following articles:
Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells
Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis
Nuclear Receptor Signaling and Cardiac Energetics
Daniel Kelly Guest Editor
| Abstract |
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,
, and ß/
as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPAR
,
, and ß/
subtypes are
60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPAR
is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPAR
controls expression of genes implicated in lipid metabolism. PPAR
, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPAR
include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxy
12,14-prostaglandin J2, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARß/
are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARß/
stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPAR
and PPAR
activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARß/
agonists on atherogenesis. Given the widespread use of PPAR
and PPAR
agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.
Key Words: peroxisome proliferator-activated receptors vascular cells arteriosclerosis diabetes lipid metabolism
| Introduction |
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The PPAR family consists of three members,
,
, and ß/
, which share
60% to 80% homology in their ligand- and DNA-binding domains. Although presently there are no proven pathways for endogenous ligands in vivo, all PPARs are activated by fatty acids (FAs). However, subtle differences in ligand and target gene specificity exist between the PPAR isoforms. PPAR
can be activated by certain polyunsaturated FAs, including DHA and EPA, by oxidized phospholipids, by lipoprotein lipolytic products,5 and by fibrates, such as fenofibrate and gemfibrozil.6,7 Fibrates are clinically used to treat patients with lipid disorders and have been shown to reduce cardiovascular mortality. PPAR
regulates genes that are involved in lipid and lipoprotein metabolism (Figure 2A).
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Natural ligands for PPAR
are the prostaglandin D2 derivative 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) and forms of oxidized linoleic acid, 9- and 13(S)-HODE, and although these endogenous ligands can activate PPAR
in vitro, presently there are no proven pathways in vivo. Synthetic ligands for PPAR
include the antidiabetic thiazolidinediones (glitazones), such as troglitazone, rosiglitazone, and pioglitazone.810 These insulin-sensitizing drugs reduce peripheral insulin resistance and thus lower blood glucose levels in patients with type 2 diabetes. Troglitazone has been the first agent of this class on the market but was withdrawn because of liver toxicity. The presently available agents, rosiglitazone and pioglitazone, do not exhibit such undesirable side effects. The underlying mechanisms of glitazone-mediated improvement of insulin resistance are not completely understood but likely occur via activation of PPAR
in adipose tissue, where it is a crucial regulator of adipogenesis.11 The induction of fat cell differentiation from large insulin-resistant adipocytes to smaller, more insulin-sensitive cells seems to be of particular importance. As a consequence of PPAR
activation, there is a reduced release of free FAs and insulin resistancemediating adipocytokines, such as tumor necrosis factor (TNF)-
, leptin, or resistin, and an increased production of the antiatherogenic, antidiabetic adiponectin. These changes are thought to lead to improved insulin sensitivity in liver and skeletal muscle (Figure 2B). In addition, although studies using muscle-specific PPAR
-deficient mice yielded controversial results with respect to the response to glitazone treatment, these mice exhibit basal insulin resistance, suggesting a role for PPAR
also in muscle.12,13
The recent development of high-affinity synthetic agonists and genetically modified animal models for PPARß/
has helped to start elucidating its (patho)physiological function. As PPAR
, PPARß/
plays a role in lipid metabolism by stimulating FA oxidation in heart and skeletal muscle cells.14 PPARß/
agonists normalize the lipid profile in db/db mice15 and obese Rhesus monkeys.16 Interestingly, PPARß/
overexpression reversed the obese phenotype in db/db mice,17 and PPARß/
agonist treatment reversed the diet-induced obesity and insulin resistance in mice.18 Thus, PPARß/
has been proposed as a pharmacological target for the treatment of obesity, insulin resistance, and dyslipidemia. Such effects may contribute to potential vascular antiatherogenic effects of such compounds (Figure 2C).
PPAR and Atherogenesis
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in vascular biology. Based on the findings that endothelial cells (ECs),19,20 vascular smooth muscle cells (VSMCs),21,22 monocytes/macrophages,23,24 and T cells25 all express PPAR
, it is clear that PPAR
activators act on a variety of vascular cells. In human ECs, PPAR
activators interfere with processes involved in leukocyte recruitment and cell adhesion. Leukocytes, mainly monocytes and T cells, are attracted to sites of developing lesions by chemotactic proteins released from ECs and cells in the subendothelium.26 Once attracted by these chemokines, leukocytes bind to endothelial adhesion molecules, which facilitate rolling, adhesion, and subsequent migration into the vessel wall.27 Synthetic PPAR
agonists, like fenofibric acid or WY14643, decrease cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1), thus limiting the adhesion of monocytic cells to stimulated ECs.20 At least in part, this regulation of VCAM-1 expression by PPAR
might be attributable to an inhibition of nuclear factor
B (NF-
B) activation in the VCAM-1 promoter. Conflicting data exist concerning the effect of PPAR
activators on endothelial chemokine expression. Stimulation of PPAR
in human ECs did not affect interferon (IFN)
induced expression of the T cellspecific CXC-chemokines IP-10, Mig, and I-TAC, nor the expression and release of monocyte chemotactic protein-1 (MCP-1), a monocyte-specific chemokine.28 In contrast to these data, it was reported that oxidized phospholipids can activate PPAR
in ECs, leading to the induction of MCP-1 and interleukin (IL)-8 expression, suggesting potential proinflammatory effects of PPAR
in these cells.29 In general, the antiinflammatory action of PPARs in vitro seems to be dependent on the particular cell and tissue type as well as the particular target gene. Therefore, studies using in vivo models of atherosclerosis are required to assess whether a global proatherogenic or antiatherogenic action exists.
ECs regulate vascular tone by balancing the release of the mediator of vasodilation, nitric oxide (NO), on the one hand, and endothelin-1 (ET-1), a regulator of vascular tone and VSMC proliferation, on the other hand. NO synthesis in these cells is regulated by endothelial NO synthase. A disturbance of NO release, for example, in the context of a lipid disorder, is associated with endothelial dysfunction and local lesion development. Both synthetic and natural PPAR
agonists, such as fenofibrate and EPA, have been shown to enhance endothelial NO synthase expression and NO release, suggesting a vasoprotective effect.30,31 In other studies, synthetic PPAR
activators, such as fenofibric acid or WY14643, diminished thrombin-induced and oxidized low-density lipoprotein (LDL)-induced expression of ET-1.32,33 Taking these effects on NO release and ET-1 expression together, PPAR
activators may counterbalance endothelial dysfunction at different steps.
In VSMCs, PPAR
activators modify inflammatory VSMC activation by inhibiting IL-1induced production of IL-6 and prostaglandins and by reducing the expression of cyclooxygenase-2 (COX-2).21
The role of PPAR
in monocytes and macrophages has been examined with respect to its effects on foam cell formation and lipid metabolism as well as its antiinflammatory properties. After adhesion to the endothelium, monocytes enter the subendothelial space, where they take up cholesterol from trapped, modified LDL to be transformed into foam cells. PPAR
is present in monocytes, and its expression is upregulated during differentiation into macrophages,34 where it may control lipid homeostasis. PPAR
activators induce the expression of the HDL receptor CLA-1/SRB-I and ABCA1, a transporter controlling apolipoprotein (apo) A-Imediated cholesterol efflux.35,36 Because this receptor is involved in cholesterol efflux, PPAR
may have a beneficial effect on the regression of fatty streaks by promoting removal of unesterified cholesterol from macrophages. Moreover, PPAR
ligands downregulate the expression of the apoB48-remnant receptor in differentiated macrophages and reduce the uptake of glycated LDL and triglyceride (TG)-rich remnant lipoproteins.37,38 This may be particularly important in patients with diabetes and the metabolic syndrome. Conflicting results exist on the role of PPARs on expression and activation of LPL, with data demonstrating a decreased secretion and activity of LPL38 on treatment with PPAR
ligands and other studies reporting that PPARs may upregulate LPL expression in macrophages.39 In this context, Ziouzenkova et al5 have shown that lipolysis of triglyceride-rich lipoproteins generates PPAR ligands, suggesting a potentially important link between lipoprotein metabolism and distal PPAR
transcriptional effects. Moreover, PPAR
regulates macrophage intracellular cholesterol metabolism and decreases the ratio of intracellular cholesteryl ester to free cholesterol by reducing acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) activity.40 Together, these data support an essential role for PPAR
in macrophage transitions by increasing the macrophage-free cholesterol pool available for cholesterol efflux and subsequent reverse transport while decreasing macrophage lipid accumulation and ensuing foam-cell formation.
During atherogenesis, monocyte/macrophage activation is of particular importance in the formation of advanced lesions. At this stage, the atherosclerotic lesion is characterized by the presence of a large necrotic lipid core, which is covered by a fibrous cap consisting of VSMCs and extracellular matrix. Thinning of the fibrous cap renders the plaque more vulnerable, thus increasing the risk of plaque rupture with subsequent thrombus formation with the clinical correlate of an acute coronary syndrome (ACS). Monocyte/macrophages accumulate in the shoulder region of advanced plaques and their presence largely contributes to plaque rupture and the development of ACS. Besides releasing matrix-degrading enzymes, these cells exhibit procoagulant activity by expressing tissue factor (TF) on their surface.41 PPAR
agonists reduce TF and matrix metalloproteinase (MMP) expression in monocytes and macrophages, thus potentially modifying the stability and thrombogenicity of atherosclerotic lesions.23,24,42 Besides these effects, PPAR
and PPAR
activation in combination with TNF-
and IFN-
may promote monocyte apoptosis.34 If properly controlled, such induced apoptosis could contribute to the stabilization of atherosclerotic lesions by eliminating a source of inflammatory cytokines and matrix degrading enzymes, although alternative, less-beneficial scenarios could also be envisaged.
T lymphocytes contribute to the vascular inflammatory response during initial atherogenesis. T lymphocytes, mainly CD4-positive cells, enter the vessel wall as naive Th0-cells and differentiate in the subendothelium to Th1-cells under the influence of certain antigens like oxidized LDL.43 Th1-cells release a variety of proinflammatory cytokines, such as IFN-
, TNF-
, or IL-2, which then stimulate other cells in the vessel wall. Activators of PPAR
and PPAR
limit this expression of deleterious Th1-cytokines, suggesting a modulating function of PPARs at a nodal point of vessel wall inflammation.25
Preclinical/Clinical Data
In clinical trials, fibrates have been shown to reduce the progression of coronary atherosclerosis in the Bezafibrate Coronary Atherosclerosis Intervention Trial,44 Diabetes Atherosclerosis Intervention Study,45 and Lopid Coronary Angiography Trial46 and to decrease the incidence of coronary heart disease in the Helsinki Heart Study47 and in Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT).48 Moreover, genetic studies on PPAR
polymorphisms suggest an association between PPAR
variants and the risk of coronary atherosclerosis and ischemic heart disease.49 Treatment of patients with type 2 diabetes with different fibrates (eg, ciprofibrate, gemfibrozil, and fenofibrate) results in improved postischemic flow-mediated dilatation of the brachial artery,5052 a NO-mediated vascular response. In fibrate-treated nondiabetic subjects with dyslipidaemia53 or coronary disease,54 similar improvements in endothelial function have also been observed in other vascular beds. Assessment of an antiatherogenic activity of PPAR
agonists in rodent models of atherosclerosis is hampered by the fact that (1) rodents develop a proinflammatory peroxisome proliferative response in the liver and (2) classically used animal models such as the LDL-receptor or apoE-deficient mouse display an aberrant hyperlipidemic response to these hypolipidemic drugs. Nevertheless, a few studies reported on the effect of PPAR
activation on atherosclerosis development in vivo in mice. PPAR
-deficient mice crossed with apoE-deficient mice exhibited less insulin resistance and demonstrated reduced atherosclerosis compared with their PPAR
+/+/apoE/ littermates.55 In addition, ciprofibrate treatment was reported to markedly increase plasma levels of atherogenic lipoproteins in apoE-deficient mice and aggravate atherosclerosis development.56 On the other hand, fenofibrate administration to Western dietfed, apoE-deficient mice resulted in decreased atherogenesis in the descending aorta but not in the aortic sinus. Because there were no major changes in plasma lipids, a direct vascular effect of PPAR
seemed to be implicated.57 Most relevant to the human situation, fenofibrate treatment of apoE2 knock-in mice, a mouse model of mixed dyslipidemia, resulted in significantly reduced atherosclerotic lesion size in the aortic sinus (A. Tailleux, G. Torpier, H. Mezdour, P.J.-C. Fruchart, B. Staels, and C. Fievet, unpublished observation, 2004). Therefore, it appears that in association with a reduction in plasma TG and nonHDL-C and an increase in HDL-C, both lipid-dependent and direct vascular effects of PPAR
contribute to its actions on atherosclerosis development in vivo. Although the data on the actions of PPAR
on atherosclerosis development in rodents are not entirely clear, the human studies conducted so far suggest that fibrates will prevent coronary atherosclerosis progression and coronary heart disease events, especially in populations with the proinflammatory conditions of diabetes (Diabetes Atherosclerosis Intervention Study and VA-HIT) and insulin resistance (VA-HIT).
The effects of PPAR
activation on cardiac function have recently also been examined in animal models of cardiovascular disease (eg, ischemic injury and ventricular hypertrophy). Left ventricular hypertrophy (LVH) occurs after prolonged pressure overload related to physiological (exercise) or pathological (hypertension) stimuli and may result in contractile dysfunction and ultimately heart failure. In the hypertrophied heart, PPAR
expression and activity are reduced, leading to altered substrate utilization.58,59 This downregulation of PPAR
signaling appears essential to preserve heart function against pressure overload.60 Conversely, cardiac PPAR
overexpression led to lipid accumulation and ventricular dysfunction, a phenotype further enhanced in the diabetic heart.61,62 However, it is possible that the systemic lipid-lowering actions of PPAR
activators leading to reduced TG delivery to extrahepatic tissues (eg, cardiac muscle) might counterbalance these alterations in cardiac PPAR
signaling in patients with diabetes.62 A recent genetic study showed an association between polymorphisms in the PPAR
gene and the extent of LVH in response to training and hypertension, demonstrating a link between PPAR
and LVH also in humans.63
If prolonged, left ventricular dilatation may result in cardiomyocyte hypertrophy (referred to as vascular remodeling) and interstitial fibrosis of the myocardium, progression to heart failure, and, eventually, sudden death. Interestingly, PPAR
agonists decrease endothelin-1induced myocyte hypertrophy in vitro64 and prevent cardiac remodeling and interstitial fibrosis in rat models of hypertension.65,66 Furthermore, PPAR
agonists reduce infarct size after ischemia/reperfusion injury and improve contractile recovery as well as endothelial function in vivo.67 Interestingly, PPAR
-deficient mice are more susceptible to ischemic damages compared with wild-type mice.68 Whether these beneficial effects of PPAR
activation on heart function are attributable to its effects on lipid metabolism or the control of vascular inflammatory response, vascular tone, and redox balance69 is presently unknown.
PPAR and Atherogenesis
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is also expressed in ECs, VSMCs, macrophages, and T cells.7073 In vitro experiments using human saphenous vein ECs indicated that activation of PPAR
, but not PPAR
, inhibits IFN-
induced expression of IP-10, Mig, and I-TAC, with a subsequent decrease in lymphocyte chemotaxis.28 Inhibition of IP-10, Mig, and I-TAC release from human ECs by PPAR
activators might therefore mainly limit the recruitment of activated T cells. Similar to PPAR
activators, PPAR
may act as a vasorelaxant, as evidenced by the inhibition of spontaneous and insulin-induced expression of ET-1 in ECs32 and by enhancing the release of NO from these cells.74 In hypertensive rats, glitazones diminished hypertension progression and prevented vascular remodeling. In these animals, glitazone treatment decreased ET-1 production and blunted production of oxygen free radicals.66 Controversial data exist on the role of PPAR
activators in endothelial apoptosis. 15d-PGJ2 and ciglitazone have been shown to induce apoptosis,75 whereas a recent study suggests protective, antiapoptotic effects of glitazones in rat ECs.76 The nature of the activators used in these studies may explain this discrepancy, especially given that some of their effects may be PPAR
independent. In addition, the expression level of PPAR
may vary in cells from different vascular beds and may also depend on the proliferative status of these cells,77 which may result in changeable levels of susceptibility toward PPAR
activators.
Other studies have examined the role of PPAR
in angiogenesis and the promotion of growth factor expression. Xin et al78 demonstrated that PPAR
activators inhibit VEGF receptor 1 and 2 expression and reduce endothelial tube formation in vitro and provided evidence that PPAR
activators might limit angiogenesis in rats. These data are in line with results from Goetze et al79 showing a reduction of leptin- and VEGF-induced migration of human ECs by PPAR
agonists. Because neovascularization may contribute to plaque progression as well as aneurysm formation and intraplaque hemorrhage, PPAR
activators might have protective effects in these settings. On the other hand, inhibiting neoangiogenesis may have less favorable effects with respect to collateral formation in patients with coronary heart disease, and therefore the definitive role of PPAR
activation in this context remains to be determined. In line with potential atheroprotective effects of PPAR
are studies showing reduction of endothelial intracellular adhesion molecule-1 and VCAM-1 expression by troglitazone or 15d-PGJ2, potentially leading to reduced monocyte/macrophage recruitment and accumulation in a mouse model of atherosclerosis.80,81
VSMCs may also be an important target of PPAR
activators. As such, PPAR
activators inhibit VSMC migration,82 the release of matrix-degrading enzymes,22 and the expression of the angiotensin II type 1 receptor.83 These effects might modulate fatty streak formation and potentially attenuate the arterial response to injury that occurs after coronary intervention. Recent work has implicated PPAR
-dependent pathways in the induction of a differentiated phenotype in proliferative VSMCs. Abe et al84 demonstrated an upregulation of smooth muscle myosin heavy chain and smooth muscle
actin, two specific markers of differentiated VSMCs. This differentiation seems, at least in part, to be mediated by GATA-6dependent transcriptional mechanisms. Interestingly, Bishop-Bailey et al85 reported increased functional PPAR
in intimal compared with medial VSMCs in rats, potentially reflecting a distinct differentiation status of VSMCs at these locations in the vessel wall. Recent studies highlighted the role of PPAR
in DNA replication and cell-cycle progression in VSMCs. Glitazones were shown to inhibit VSMC growth and proliferation through increased levels of the cyclin-dependent kinase inhibitor p2786 and decreased phosphorylation of the retinoblastoma protein, thus leading to cell-cycle arrest.87,88 In addition, glitazones induce cell apoptosis by increasing the expression of the growth arrest and DNA damage-inducible 45 gene in an Oct-1dependent manner.89 Pharmacological and genetic approaches demonstrated that PPAR
activation blocks cell-cycle progression and DNA replication by an additional mechanism involving inhibition of platelet-derived growth factor and insulin-induced minichromosome maintenance protein expression as well as interference with E2F signaling.87
In cells of the monocytic lineage, PPAR
mRNA and protein is present, and its levels increase with differentiation to macrophages.90 Several studies suggest antiinflammatory and potential antiatherogenic effects of PPAR
activators in these cells. The first demonstration of antiinflammatory PPAR
effects in monocyte/macrophages showed that PPAR
activators inhibit expression of inducible nitric oxide synthase (NOS), scavenger receptor A, and gelatinase B/MMP-9 in monocytes,91 as well as monocyte cytokine expression.71 In addition, PPAR
activators decrease osteopontin expression, enhance the release of the antiinflammatory cytokine IL-1 receptor antagonist, and limit the expression of myosin heavy chain class II markers, suggesting a broad antiinflammatory effect of PPAR
in these cells.92 PPAR
also regulates macrophage lipid homeostasis. On the one hand, PPAR
activators may promote the regression of fatty streaks by increasing the removal of cholesterol from macrophages via the induction of the expression of the HDL receptor CLA-1/SRB-I, ABCA1, ABCG1, and apoE.35,93,94 On the other hand, however, PPAR
may also display deleterious effects by increasing the expression of the oxidized LDL scavenger receptor CD36,95 which may promote foam cell formation. Still, recent data have evidenced that PPAR
activation does not promote global lipid loading and transformation of macrophages into foam cells.36 Moreover, conditional disruption of PPAR
in macrophages led to lowered expression of the PPAR
target genes CD36 and ABCA1 and reduced cholesterol removal from macrophages.94 Transplantation of PPAR
-deficient bone marrow cells in irradiated LDL-receptordeficient mice resulted in a significant increase in atherosclerotic lesions.93 In addition, activation of PPAR
led to decreased SRAI/II activity and resulted in decreased intracellular cholesteryl ester accumulation.96 PPAR
ligands also decrease glycated LDL uptake,38 and, as PPAR
, PPAR
decreases macrophage apoB48 receptor expression and TG accumulation.37 Taken together, these data suggest an overall beneficial effect of PPAR
activators on fatty streak formation and atherosclerosis development (Figure 3).
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In CD4-positive lymphocytes, various groups have shown that PPAR
activators modulate the expression of proinflammatory Th1 cytokines. As such, glitazones as well as the naturally occurring ligand 15d-PGJ2 reduce IL-2 secretion from murine T-cell clones97 and human T cells and decrease cell proliferation73 Data from an inflammatory mouse model suggest that such a reduction in Th-1 cytokine expression is attributable to a shift toward Th2 cytokine dominance.98 In addition, PPAR
activators limit the expression of IFN-
and TNF-
, thus reducing the proinflammatory activity of T cells toward monocytes and ECs.25 Moreover, the direct effects of PPAR
on Th1 cytokine expression in T cells may be fostered by an inhibitory effect of PPAR
activators in dendritic cells, where glitazones reduce IL-12 secretion, an important Th1 response-driving factor.99
Preclinical/Clinical Data
The effect of PPAR
activators on vascular disease has been examined in various animal models. Law et al100 were the first to report a reduction of intimal hyperplasia in a rat vascular injury model after troglitazone treatment. The effects of PPAR
activators on lesion development were also examined. Li et al101 reported that synthetic PPAR
activators reduced lesion size in male LDL receptordeficient mice. Interestingly, no significant effect was seen in female mice, indicating a sexual dimorphism in response to PPAR
agonists. The decrease in lesion size was associated with decreased expression of TNF-
, reflecting a reduction of the inflammatory response in the vessel wall. In this model, glitazone treatment increased CD36 expression in the vessel wall despite a decrease in overall lesion size. Other groups investigated glitazone effects in apoE-deficient mice and observed similar decreased atherosclerosis in these animals.102,103
Several studies have assessed the effects of glitazones in animal models of ischemia/reperfusion injury and demonstrated their potential benefit in improving contractile function and postischemia heart rate recovery.68,104,105 In addition, glitazones decrease myocyte hypertrophy,106,107 and PPAR
ligands also attenuate myocardial infarctioninduced left ventricular dilatation and myocyte hypertrophy and normalize contractile function in vivo in mice.108 Several potential mechanisms may underlie these beneficial actions of glitazones on cardiac function, including antiinflammatory properties on NF-
B/AP-1 as well as decreased production of ET-1 and NO. Thus, PPAR
activation may improve myocardial function, an effect of particular interest for patients with diabetes who are at great risk for myocardial injury.
Although outcome data on the effects of PPAR
activators on cardiovascular mortality are lacking so far, various studies have focused on surrogate markers of atherosclerosis. Studies show that glitazone treatment improves endothelium-dependent vasodilatation but did not affect endothelium-independent vasodilatation,109 suggesting that glitazones act by improving endothelial function. This might be of particular importance in the high-risk population of patients with diabetes, because these patients exhibit early endothelial dysfunction.110 Further evidence of vasoprotective effects of glitazones came from studies with inflammatory surrogate parameters of arteriosclerosis in patients with diabetes, such as C-reactive protein, serum amyloid A, TNF-
, or E-selectin, all known to predict the risk of cardiovascular events in patients.26 Treatment of patients with type 2 diabetes with glitazones significantly reduced C-reactive protein levels as well as white blood cell count and MMP-9 serum levels.111 In addition, a randomized, placebo-controlled trial in patients with coronary artery disease and type 2 diabetes mellitus demonstrated a significant reduction of serum amyloid A after only 2 weeks of rosiglitazone treatment and a significant decrease in TNF-
levels after 6 weeks, suggesting an effect independent of the metabolic changes induced by the treatment.112 Patients with type 2 diabetes exhibit elevated levels of other markers, such as sCD40L, MMP-2, MMP-3, and MMP-9, likely reflecting the increased cardiovascular risk of these patients.112,113 Glitazone treatment decreased sCD40L levels as well as serum levels of MMP-9 as early as 2 weeks after the initiation of treatment.113 Interestingly, previous studies have shown that glitazones exhibit maximal glucose-lowering effects only after 8 to 12 weeks.114 This difference in the reduction of sCD40L or MMP-9 and glucose strongly suggests that glitazones might directly affect levels of these biomarkers independent of their metabolic action.
In addition to these indirect markers of vascular disease, glitazones influence structural changes in arteriosclerosis and restenosis. In a small clinical study including 135 Japanese patients with diabetes, troglitazone treatment reduced intimal and medial complex thickening in carotid arteries, as determined by B-mode ultrasound.115 Preliminary data with other glitazones showed similar effects on IMT,116 suggesting that these structural changes in the vessel wall may be a class effect of these drugs. Given the increased risk of patients with type 2 diabetes to develop restenosis after angioplasty and given the in vitro and in vivo effects of glitazones on smooth muscle cell proliferation and intimal hyperplasia, both critical contributors to restenosis, a Japanese group studied the effect of troglitazone treatment on coronary artery restenosis. After 6 months, compared with placebo, troglitazone significantly reduced narrowing of the coronary lumen.117 However, at this time, it is not known whether treatment of patients with glitazones will reduce cardiovascular mortality, especially taking into consideration the side effects of these agents, such as fluid retention. Large clinical trials are underway and will demonstrate whether these vasculoprotective effects of glitazones may modulate the clinical outcome in the high-risk population of patients with type 2 diabetes (online Table 1, available at http://circres.ahajournals.org).
PPARß/ and Atherogenesis
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has been performed in cells of the monocytic lineage. Although conflicting data exist, a role for PPARß/
in macrophage lipid homeostasis has been demonstrated. On the one hand, PPARß/
may promote very-low-density lipoprotein (VLDL) triglyceride and cholesterol loading and storage in macrophages via the induction of scavenger receptors CD36 and SRA as well as ADRP and A/FABP expression.118,119 On the other hand, PPARß/
activation increases ABCA1 expression and apoA-Imediated cholesterol efflux.16,118 In sharp contrast to these findings, a recent report failed to demonstrate any effect of PPARß/
on macrophage cholesterol homeostasis.3 Besides these effects on macrophage cholesterol homeostasis, a possible role for PPARß/
in the control of macrophage inflammation is also emerging. As such, PPARß/
activators exert antiinflammatory effects by diminishing LPS-induced inducible NOS and Cox-2 expression.92 Although deletion of PPARß/
in macrophages results in a lower inflammatory response, suggesting that PPARß/
is proinflammatory, incubation of macrophages with a synthetic PPARß/
ligand also decreases the production of inflammatory molecules.3 These apparently paradoxical observations are attributable to an original mechanism of transcription control by PPARß/
that depends on whether the receptor is bound to a ligand. In the absence of ligand, PPARß/
sequesters a transcriptional repressor of inflammatory response genes, called BCL-6. Therefore, in the absence of PPARß/
, BCL-6 actively represses inflammation. However, in the presence of ligand and receptor, a molecular switch occurs and this repressor is released from PPARß/
and subsequently exerts antiinflammatory activities. In ECs, the synthetic PPARß/
activator L-165041 reduced cytokine-induced VCAM-1 expression as well as the secretion of MCP-1, thus modulating monocyte adhesion to activated ECs.120 To date, nothing is known about the role of PPARß/
in smooth muscle cells and T lymphocytes.
Preclinical/Clinical Data
In a mouse model of atherosclerosis, transplantation with bone marrow isolated from PPARß/
-deficient mice resulted in reduced atherogenesis, most likely through an increased availability of the inflammatory suppressor BCL-6.3 To date, the influence of systemic administered PPARß/
activators on atherosclerosis has not been reported. Data from clinical studies using PPARß/
agonists are presently also lacking.
| Therapeutic Perspectives |
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effects on glucose metabolism without stimulating adipocyte differentiation. The development of SPPARMs is therefore an exciting area of research with potentially large clinical application.
Combined PPAR
/PPAR
Agonists
Given the favorable metabolic effects of both PPAR
and PPAR
activators as well as their potential to modulate vascular disease, combined PPAR
/
activation has recently emerged as an intriguing concept, leading to the development of mixed PPAR
/
activators. Preclinical data in rodents have demonstrated that several of these activators improve insulin sensitivity, as well as FA, glucose, and lipoprotein metabolism.123,124 In addition, clinical data from phase II trials with agents such as ragaglitazar confirmed these beneficial effects on insulin sensitivity and HDL and triglyceride levels in patients. However, several patients experienced major side effects, with massive weight gain, appearance of edema, and heart failure, leading to interruption of the development of certain of these agents. Moreover, some of these combined PPAR
/
activators have led to tumor development in treated animals. Still other combined PPAR
/
activators, such as tesaglitazar, are presently being examined in phase III trials. To overcome the unfavorable action of these agents, several laboratories are now focusing on partial PPAR
/
activators, which may combine the beneficial metabolic effects of PPAR
and PPAR
activation with fewer undesirable side effects.
PPAR activation in the cardiovascular system has emerged over the past few years as an intriguing concept to modulate various processes in the development of vascular disease and heart failure. Some data on the overall effect of PPARs in vascular disease remain controversial, but the presently ongoing trials with PPAR
and PPAR
activators (online Table 1) will address some of the open questions and prove whether the concept of PPAR activation will translate into improved patient care and potentially broaden the indication spectrum of these PPAR activators.
| Acknowledgments |
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| Footnotes |
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| References |
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3. Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM. Transcriptional repression of atherogenic inflammation: modulation by PPAR
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4. Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT, Parks DJ, Moore JT, Kliewer SA, Willson TM, Stimmel JB. Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPAR
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5. Ziouzenkova O, Perrey S, Asatryan L, Hwang J, MacNaul KL, Moller DE, Rader DJ, Sevanian A, Zechner R, Hoefler G, Plutzky J. Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Proc Natl Acad Sci U S A. 2003; 100: 27302735.
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N. Hennuyer, A. Tailleux, G. Torpier, H. Mezdour, J.-C. Fruchart, B. Staels, and C. Fievet PPAR{alpha}, but not PPAR{gamma}, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1897 - 1902. [Abstract] [Full Text] [PDF] |
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J. Hetzel, B. Balletshofer, K. Rittig, D. Walcher, W. Kratzer, V. Hombach, H.-U. Haring, W. Koenig, and N. Marx Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1804 - 1809. [Abstract] [Full Text] [PDF] |
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B. Staels and J.-C. Fruchart Therapeutic Roles of Peroxisome Proliferator-Activated Receptor Agonists Diabetes, August 1, 2005; 54(8): 2460 - 2470. [Abstract] [Full Text] [PDF] |
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R. Nasrallah and R. L. Hebert Prostacyclin signaling in the kidney: implications for health and disease Am J Physiol Renal Physiol, August 1, 2005; 289(2): F235 - F246. [Abstract] [Full Text] [PDF] |
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E. L. Schiffrin More Evidence of Cardiorenal Protective Effects of Peroxisome Proliferator-Activated Receptor Activation Hypertension, August 1, 2005; 46(2): 267 - 268. [Full Text] [PDF] |
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D. Hamerman Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies QJM, July 1, 2005; 98(7): 467 - 484. [Abstract] [Full Text] [PDF] |
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B. Cariou, J.-C. Fruchart, and B. Staels Review: Vascular protective effects of peroxisome proliferator-activated receptor agonists The British Journal of Diabetes & Vascular Disease, May 1, 2005; 5(3): 126 - 132. [Abstract] [PDF] |
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J.-H. Kim, K. Yamaguchi, S.-H. Lee, P. K. Tithof, G. S. Sayler, J.-H. Yoon, and S. J. Baek Evaluation of Polycyclic Aromatic Hydrocarbons in the Activation of Early Growth Response-1 and Peroxisome Proliferator Activated Receptors Toxicol. Sci., May 1, 2005; 85(1): 585 - 593. [Abstract] [Full Text] [PDF] |
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B. C. Blaxall, J. M. Miano, and B. C. Berk Angiotensin II: A Devious Activator of Mineralocorticoid Receptor-Dependent Gene Expression Circ. Res., April 1, 2005; 96(6): 610 - 611. [Full Text] [PDF] |
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E. L. Schiffrin Peroxisome proliferator-activated receptors and cardiovascular remodeling Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1037 - H1043. [Abstract] [Full Text] [PDF] |
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F. J. Schopfer, Y. Lin, P. R. S. Baker, T. Cui, M. Garcia-Barrio, J. Zhang, K. Chen, Y. E. Chen, and B. A. Freeman Nitrolinoleic acid: An endogenous peroxisome proliferator-activated receptor {gamma} ligand PNAS, February 15, 2005; 102(7): 2340 - 2345. [Abstract] [Full Text] [PDF] |
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I. J. Kullo and C. M. Ballantyne Conditional Risk Factors for Atherosclerosis Mayo Clin. Proc., February 1, 2005; 80(2): 219 - 230. [Abstract] [PDF] |
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P. R. Moreno and V. Fuster The year in atherothrombosis J. Am. Coll. Cardiol., December 7, 2004; 44(11): 2099 - 2110. [Full Text] [PDF] |
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D. Walcher and N. Marx Insulin resistance and cardiovascular disease: the role of PPAR{gamma} activators beyond their anti-diabetic action Diabetes and Vascular Disease Research, October 1, 2004; 1(2): 76 - 81. [Abstract] [PDF] |
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D. S. Ory Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis: Have the Orphans Found a Home? Circ. Res., October 1, 2004; 95(7): 660 - 670. [Abstract] [Full Text] [PDF] |
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N. Marx, D. Walcher, N. Ivanova, K. Rautzenberg, A. Jung, R. Friedl, V. Hombach, R. de Caterina, G. Basta, M.-P. Wautier, et al. Thiazolidinediones Reduce Endothelial Expression of Receptors for Advanced Glycation End Products Diabetes, October 1, 2004; 53(10): 2662 - 2668. [Abstract] [Full Text] [PDF] |
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