STATE-OF-THE-ART PAPER
Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease
Andries J. Gilde, PhD*, ,
Jean-Charles Fruchart, PhD*,, and
Bart Staels, PhD*,,,*
* INSERM U545
Department of Atherosclerosis, Institut Pasteur de Lille
University of Lille 2, Lille, France
Manuscript received November 29, 2005;
revised manuscript received April 11, 2006,
accepted April 18, 2006.
* Reprint requests and correspondence: Dr. Bart Staels, U545 INSERM, Institut Pasteur de Lille, 1 Rue du Professor Calmette B.P. 245, Lille, F-59019 France. (Email: Bart.Staels{at}pasteur-lille.fr).
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Abstract
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Since their discovery in the early 1990s, the members of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors have been recognized as therapeutic targets against dyslipidemia and diabetes. Recent studies also identified anti-inflammatory actions of PPARs in cells constituting the atherosclerotic lesion. Delineation of this activity extended the therapeutic potential of PPAR activators beyond their original design as metabolic controllers. The PPAR family consists of 3 PPAR isoforms:  , ß/ , and  , which exert different and sometimes overlapping effects on whole-body physiology in particular on lipid and glucose metabolism. This review summarizes the current knowledge on the role of PPARs in cardiovascular disease, the metabolic syndrome, atherosclerosis, and cardiac function.
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Abbreviations and Acronyms
| | CVD = cardiovascular disease | | HDL = high-density lipoprotein | | IL = interleukin | | LDL = low-density lipoprotein | | PPAR = peroxisome proliferator-activated receptors | | SPPARM = selective peroxisome proliferator-activated receptors modulator | | TZD = thiazolidinedione |
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In 1990, Issemann and Green (1) discovered the mechanism by which peroxisome proliferation in the liver was induced by hypolipidemic drugs and plasticizers (2). This pioneering research paved the way to the current understanding of the physiological function of the peroxisome proliferator-activated receptors (PPARs). The PPARs belong to the nuclear receptor superfamily of transcription factors. Since their discovery, they have received increasing attention as potential pharmacologic targets for combating obesity and diabetes (3). The PPAR family consists of 3 isoforms (i.e., PPAR, PPARß [also known as ], and PPAR), each with their own tissue distribution pattern (4–6). Whereas PPAR is predominantly expressed in tissues with a high oxidative capacity such as the heart and liver, PPAR is highest expressed in adipose tissue, and the expression of PPARß/ is more ubiquitous, being highest in skeletal muscle and intestine. The PPARs can be activated by an array of natural (endogenous) ligands, ranging from long-chain fatty acids to eicosanoids, that all bind with different affinity (7–9). In addition, synthetic ligands have been designed for the 3 PPAR isoforms with the purpose of therapeutic application. On ligand-binding, PPARs transactivate gene expression by heterodimerization with another member of the nuclear receptor superfamily, the retinoic X receptor, and this complex binds to a direct repeat sequence designated PPAR-responsive element (Fig. 1). Alternatively, PPARs are able to down-regulate or transrepress gene expression via a signal-transduction disrupting mechanism independent of DNA binding (10).
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Figure 1 Schematic representation of the transcriptional action of peroxisome proliferator-activated receptors (PPARs) with their heterodimer partner retinoic X receptor (RXR) and their major physiological functions. *Major function for this isoform but not exclusive. L = ligand; PPRE = peroxisome proliferator-activated receptor-responsive element.
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Actions of PPAR agonists
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PPAR.
For a long time, the PPAR-activating fibrates have been used in the treatment of dyslipidemia. In dyslipidemic patients, these drugs improve the plasma lipid profile by lowering triglyceride, and to a lesser extent, low-density lipoprotein (LDL) cholesterol levels and by increasing high-density lipoprotein (HDL) cholesterol levels. For unknown reasons, the HDL-increasing effect of fibrates seems less pronounced in type 2 diabetic patients (11,12). These effects are achieved by a variety of mechanisms, such as an increase in lipoprotein lipase expression, reduction of apolipoprotein (apo)CIII expression, inhibition of triglyceride synthesis, and very-low-density lipoprotein production. Furthermore, fibrates increase the expression of fatty acid metabolizing genes in oxidative tissues, resulting in an increased oxidation of fatty acids (reviewed by Chinetti-Gbaguidi et al. [13]). Treatment of hyperlipidemia to reduce the risk of cardiovascular disease (CVD) has focused predominantly on LDL cholesterol-lowering strategies, mainly by use of statins (14). However, several large studies have shown that the use of PPAR-activating drugs is favorable in the reduction of CVD risk factors, as summarized by the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) investigators (15). Furthermore, it was shown that PPAR agonists prevented the progression of arterial lumen occlusion, reduced the incidence of myocardial infarction, and reduced cardiovascular events (11,12,16–23) (Table 1). Apart from the abovementioned effects, PPAR activators favorably affect CVD by influencing atherosclerotic plaque composition (24). Recently it was shown that PPAR is expressed in cell types involved in the process of atherosclerosis. This enables this isoform to affect this process at the cellular level independent of or in addition to acting via blood lipid changes. PPAR activation reduces the infiltration of macrophages into the atherosclerotic plaque, reduces intraplaque lipid accumulation in an animal model of mixed dyslipidemia, and reduces cholesterol esterification in human macrophages caused by an increased adenosine triphosphate-binding cassette A1–mediated cholesterol efflux (24,25). Furthermore, fibrates were shown to reduce the production of proinflammatory cytokines such as interleukin (IL)-6, interferon , tumor necrosis factor , IL-1ß, and high-sensitivity C-reactive protein that may contribute to reducing the risk of cardiovascular events (10,25–27). Recently it was discovered that PPAR is regulating cell-cycle genes and cell proliferation of vascular smooth muscle cells, implying that this nuclear receptor is a therapeutic target in restenosis after coronary angioplasty (10,28).
One of the few potentially undesirable effects reported on fibrate use is the increase of plasma homocysteine that occurs via a PPAR-dependent mechanism (29). However, the clinical consequences of these findings are debatable because the increase of homocysteine levels caused by fenofibrate had no effect on the reduction of vessel lumen diameter or clinical events in DAIS (Diabetes Atherosclerosis Intervention Study) (30). A recent study suggested that homocysteine could reduce hepatic apoAI production, at least in part, by decreasing PPAR activity (31). Whether this mechanism may participate in the lack of effect of fenofibrate on apoAI in type 2 diabetic patients as observed in the recently published the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial (12) remains to be established.
Recently, emotions have risen by the reports of rhabdomyolysis as a result of the use of statins in combination with PPAR agonists (32,33). Close review of the literature showed an increased risk only on gemfibrozil use, but not with fenofibrate (34). Gemfibrozil is believed to alter statin metabolism, resulting in increased statin plasma levels (35). The risk of rhabdomyolysis was greatly reduced by using lower concentrations of statins or combining other fibrates than gemfibrozil with other statins than cerivastatin, which was removed from the market (36,37). The recent FIELD study showed no adverse effects of the combined use of statins with fenofibrate (12).
PPARß/.
Exciting new developments were reported in the field of PPARß/ research. This isoform has long been the neglected PPAR isoform because it is ubiquitously expressed, making it difficult to pinpoint ligand-mediated effects to specific tissues. With the development and use of compounds such as L165041, GW501516, and GW610742 data concerning PPARß/ function in (patho)physiology is accumulating (38). In several animal models of obesity and diabetes, it was shown that these compounds increase HDL cholesterol and decrease white adipose tissue fat deposits, triglycerides, fasting insulin, and small-density LDL, suggesting PPARß/ to be a suitable target in hyperlipidemia (39,40). Additionally, it was discovered that PPARß/ activates fatty acid oxidation in heart and skeletal muscle by increasing the expression of genes involved in fatty acid handling and changing skeletal muscle fiber type from glycolytic to oxidative (41). Altogether these studies suggest that PPARß/ is a promising new target in the battle against obesity and diabetes and subsequent CVD. Extensive research into the function of this isoform in body physiology is warranted, together with safety studies of the available agonists of PPARß/. The latter is important because PPARß/ was found to play a role in cancer in rodents (42–46).
PPAR.
The thiazolidinediones (TZDs) are PPAR ligands in clinical use as insulin sensitizing drugs for the treatment of type 2 diabetes (47). Preclinical as well as clinical data accumulate on the beneficial effects of TZDs on CVD (Table 1) (48–52). The principal mechanism by which TZDs exert their insulin sensitization effect is via the activation of PPAR in adipose tissue, resulting in improved insulin sensitivity in skeletal muscle and liver. By the induction of subcutaneous adipocyte differentiation and decreasing the visceral-to-subcutaneous adipose tissue ratio, TZDs help to store free fatty acids in less harmful depots. The TZDs on the market today are rosiglitazone and pioglitazone. These compounds have very similar activities, except on plasma lipids, which seem to be more favorably affected by pioglitazone (2,53). Although pioglitazone decreases triglyceride levels, rosiglitazone is neutral. Both drugs increase HDL cholesterol, but rosiglitazone treatment also increases LDL and total cholesterol levels. The mechanism explaining this difference is not yet clear. Although some claim pioglitazone to have, albeit limited, PPAR-activating properties, selective peroxisome proliferator-activated receptors modulator (SPPARM) effects could also be involved.
In addition to the insulin-sensitizing effect, TZDs possess anti-inflammatory properties. This, together with the discovery that PPAR is expressed in endothelial cells, macrophages, vascular smooth muscle cells, lymphocytes, and platelets, raised the hypothesis that using TZDs could be a suitable therapeutic approach to combating the development and progression of the atherosclerotic plaque (54). PPAR activation results in a decrease of matrix metalloproteinase 9 and soluble cluster of differentiation 40–ligand expression as well as reduction of plasma IL-6, IL-8, fibrinogen, and C-reactive protein levels in both type 2 diabetic and nondiabetic patients (55–58). In addition, when added to statin therapy, further atherosclerotic plaque regression was observed in vivo in rabbits using high-resolution magnetic resonance imaging (59). The recently reported PROactive Study (Prospective Pioglitazone Clinical Trial in Macrovascular Events) showed that, although the primary end point composed of hard CVD, and more subjective, procedural end points, was not reached, pioglitazone significantly decreased the hard end points of CVD (all-cause mortality, nonfatal myocardial infarction, and stroke) (51). A first post-hoc analysis of patients with myocardial infarction furthermore showed that pioglitazone significantly reduced recurrent cardiovascular events (60).
A notorious effect of TZD use is the gain of weight as a result of increased body fat and edema. Although this gain of weight is paradoxically associated with an improved clinical status of the patient, it may be undesirable from a psychological point of view. Contributing to this weight gain is the TZD-induced fluid retention partly caused by PPAR-mediated H2O and salt retention in the collecting duct of the kidney (61). This fluid retention together with increased vascular permeability may result in edema and could thus potentially, especially in type 2 diabetic patients with diminished cardiac function, precipitate congestive heart failure (62,63). The recent PROactive Study (51), investigating the use of pioglitazone in diabetic patients with macrovascular disease, showed that pioglitazone does not increase mortality caused by heart failure.
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Polymorphisms and genetic alterations of PPARs and risk of CVD
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Variations in the PPAR genes may also modulate the risk and susceptibility of disease. The use of animal models together with pharmacologic intervention provided evidence underlining the importance of the PPAR family as major players in whole-body lipid and glucose homeostasis. These observations have been extended by genetic studies in humans showing that PPARs may influence risk factors of CVD (Table 2).
PPARA.
Polymorphisms within the human PPAR gene have been reported to influence risk markers for CVD (Table 2) (64–68). The L162V polymorphism of PPAR was identified as a gain of function mutation associated with favorable differences in plasma lipid concentrations (69). Furthermore, haplotype analysis showed that the PPAR gene variation influences the onset of age-related diabetes in men (64).
In mice, genetic ablation of PPAR not only affects energy substrate metabolism by decreasing the ability to utilize fatty acids, but also impairs the immune system (70). Because both mechanisms are involved in the etiology of CVD, these observations strengthen the importance of PPAR in the process of CVD. The recently reported skeletal muscle–specific PPAR transgenic mouse model beautifully shows the complexity of physiological PPAR signaling and the necessary organ crosstalk in this process (71). This study shows an insulin-resistant phenotype in these mice. However, (pre)clinical use of fibrates has either no effect or induces a slight improvement of glucose metabolism (12,72,73).
PPARD.
Only recently are data becoming available on mutations or polymorphisms of PPARß/ (Table 2) and their influence on body homeostasis or risk of CVD. Skogsberg et al. (74) showed that of the 4 polymorphism detected in PPARß/, only +294T/C is associated with increased LDL cholesterol levels in healthy subjects. The rare C allele showed higher transcriptional activity at the promoter level that was partially mediated by an increased binding of Sp-1. Interestingly, in a Korean population, a haplotype containing 5 single nucleotide polymorphisms of PPARß/ was associated with a reduction of fasting glucose levels as well as increased body mass index in healthy volunteers (75). The clinical consequences of this polymorphism are uncertain because both parameters have opposite effects on risk for CVD (76). Further studies on PPARß/ polymorphisms are eagerly awaited.
In this respect, the data obtained from genetically altered mice are of interest. In PPARß/ null mice it was observed that gonadal adipose tissue was decreased compared with wild-type mice, and body weight tended to be decreased (significant in female mice) (77). Interestingly, adipose tissue–specific overexpression of an activated form of PPARß/ also resulted in a reduction of adipose tissue, an alteration that was shown to be protective against high-fat feeding (78). Although a function for PPARß/ in energy expenditure is established, its influence on atherosclerotic plaque formation or regression is not clear. Whereas an agonist for PPARß/ did not influence plaque progression, PPARß/ deficiency in macrophages resulted in altered atherosclerosis susceptibility (79).
PPARG.
Several polymorphisms in the PPAR gene have been detected (Table 2) (80–90). They have been reported to influence body mass index, insulin resistance, blood pressure, and the development of type 2 diabetes. Of special interest are the Pro467Leu, Val290Met, and Arg425Leu mutations because these act in a dominant-negative manner, resulting in partial lipodystrophy with severe insulin resistance (87–89). Although these PPAR mutations result in the increase of risk factors of CVD, they are very rare, limiting their epidemiologic significance in large population studies (81,91–93). Overall we can state that PPAR mutations influence the risk and development of type 2 diabetes.
Comparing the data obtained in human studies with that from animal models copying PPAR mutations allows us to propose whether polymorphisms in humans either a gain or a loss of function properties. Mice homozygous for PPAR deficiency or in which the wild-type gene is replaced by a dominant negative PPAR mutation L466A die in utero at embryonic day 10.5 to 11.5 (94). Interestingly heterozygous PPAR knockout mice are more sensitive to insulin during an oral glucose tolerance test, whereas TZD treatment normalized insulin action and high-fat feeding-induced adipose tissue hypertrophy and insulin resistance in peripheral tissues and liver in both wild-type and PPAR +/– animals (95). In addition to these whole-genome transgenic models, the tissue-specific knockout models for PPAR have proven valuable in delineating the role of this receptor in specific tissues. Skeletal muscle–specific deletion of PPAR resulted in glucose intolerance and insulin resistance (96,97). Interestingly, only 1 of these models had a response to TZD treatment, further feeding the controversy around the involvement of muscle in the insulin-sensitizing effect of TZDs. Adipose tissue–specific ablation of PPAR using the aP2-Cre system was protective against insulin resistance and body weight gain on high-fat feeding in 1 case, whereas in a comparable model high-fat feeding induced insulin resistance in fat and liver (98,99). Selective knockout in adipose tissue of the PPAR2 isoform also resulted in insulin resistance associated with reduced weight of white but not brown adipose tissue (100). Interestingly, introduction of the Pro12Ala mutation in exon B of the PPAR gene resulted in a reduced expression of both PPAR1 and PPAR2 in white and PPAR2 in brown adipose tissue (101). These hypomorphic PPAR mice were indistinguishable from wild-type littermates at birth, but became growth retarded within the first week after birth, after which 24% of the mice died. Furthermore, PPARhyp/hyp mice had less white adipose tissue and normal fasting glucose and insulin levels, which were elevated in the postprandial state compared with those of wild-type littermates. Rosiglitazone treatment only normalized glucose levels, and insulin levels remained increased. Free fatty acid levels of PPARhyp/hyp mice were increased and did not change on fasting. The lack of adipose tissue in this model was accompanied by an increased expression in skeletal muscle of PPAR and PPARß/, together with genes involved in ß-oxidation.
Altogether the data gathered using tissue-selective PPAR knockout models clearly confirm the role of this isoform in adipose tissue generation and function, but the metabolic consequences at the whole-body level remain unclear.
PPARs and cardiac function.
With the clinical application of PPAR activators in type 2 diabetic patients at high risk of developing CVD, the effects on cardiac function must be considered. Because the heart heavily relies on fatty acids as a source of energy, it is no surprise that PPAR and PPARß/ play an important role in cardiac physiology. Interestingly, the absence of PPAR was shown to be beneficial for cardiac performance after ischemia/reperfusion injury, whereas cardiac-specific overexpression of PPAR seemed to be detrimental to cardiac function (102,103). In contrast, several studies showed improved cardiac function and recovery after ischemia/reperfusion on PPAR activator treatment (104,105). Furthermore, fenofibrate was shown to protect the heart against inflammation and fibrosis in an animal hypertension model (106,107). In an in vitro cardiac-hypertrophy model, the PPAR agonists fenofibrate and Wy-14,643 and the PPARß/ agonist L165041 reduced hypertrophy, although the expression of both PPAR and PPARß/ were found to be decreased during hypertrophy (108). In contrast, in humans it was observed that protein expression of both PPAR and PPAR were increased in failing left ventricle (109).
Cardiomyocyte-specific knockout of PPARß/ resulted in lipotoxic dilated cardiomyopathy caused by a decreased expression of fatty acid handling genes (110). Recently, the development of a cardiomyocyte-specific PPAR knockout has shed some light on the role of this PPAR isoform in the heart and the cardiomyocyte in particular (111). This study shows PPAR to be a suppressor of nuclear factor (NF) B-signaling during growth and development, as can be concluded from the development of cardiac hypertrophy in knockout mice with a concomitant increase of atrial natriuretic factor expression and increased NFB activity. These results substantiate the studies of others who showed cardioprotective effects of rosiglitazone via the NFB-pathway after cardiac infarction (112,113). Overall, both vascular and cardiomyocyte-specific activation of all 3 PPAR isoforms may prove to be protective in humans. The results of the recent PROactive Study are in support of a cardioprotective activity of TZDs in type 2 diabetic patients (51).
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New concepts and therapeutic applications
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Within PPAR research, basic and translational clinical approaches resulted in new concepts that can be translated and tested into clinical practice in the near future. The following section of this review discusses some new applications and new concepts of PPAR biology.
Dual PPAR activators.
A new class of PPAR activators are the dual / agonists or glitazars. Combining the properties of different PPAR isoforms in 1 drug should yield more global effects as compared with isoform-specific agonists. In line with this presumption are the results obtained from tesaglitazar-treated rats on a high-fat diet that show improved insulin sensitivity, increased non-esterified fatty acid (NEFA) clearance in white adipose tissue, and increased NEFA use by the liver and skeletal muscle (114). Recently, clinical data on a dual PPAR/ agonist appeared. In a dose-finding study, the effects of ragaglitazar on type 2 diabetic patients was assessed for 12 weeks (115). Ragaglitazar reduced fasting plasma glucose levels and decreased triglycerides. Furthermore, a decrease was observed in total and LDL cholesterol, free fatty acids, and apoB, whereas HDL cholesterol was increased. Unfortunately, some adverse effects were reported, such as edema, anemia, and weight gain. In a multicenter double-blind placebo-controlled trial, the effect of the dual PPAR/ agonist muraglitazar (BMS-298585) was tested as monotherapy in drug-naïve individuals for 24 weeks (116). The results showed a reduction in glycosylated hemoglobin, triglycerides, total and LDL cholesterol, and apoB. Furthermore, HDL cholesterol was increased and fasting glucose, insulin, and C-peptide levels were decreased, altogether results most favorable in reducing the risk of CVD. However, like PPAR agonists, muraglitazar increases body weight as well as edema, limiting its clinical dose to 5 mg/day, a dose at which the drug likely activates PPAR predominantly. Furthermore, a recent study suggested that at the dose of 5 mg/day, muraglitazar increased the incidence of the composite end point consisting of death or major adverse cardiovascular events (myocardial infarction, stroke, transient ischemic attack, and congestive heart failure) as compared with placebo or pioglitazone (117). These studies debate the suitability of this PPAR/ agonist for clinical purposes. Compound 23 is a dual PPAR/ activator with triglyceride- and glucose-lowering as well as HDL-raising properties in zucker diabetic fatty rats (118). Recently, compound T913659 was reported to activate all 3 PPAR isoforms (panagonist) with PPAR and PPARß/ as the main targets (119). The T913659 increased HDL cholesterol levels in high-fat-fed St. Kitts Vervet monkeys, a model of nonhuman primate atherosclerosis. In perspective, bezafibrate, a relatively old fibrate, is a partial agonist for PPAR, PPARß/, and PPAR, acting thus also as a panagonist (120). Clinical studies with bezafibrate do not report edema or weight gain, promising a new future for compounds previously discarded by the industry because of their pan-PPAR action.
SPPARM.
Recently, the concept of the SPPARM was introduced. This concept encompasses the principle of chemical alteration of PPAR-specific ligands to create compounds that possess differential gene-regulating properties (121). Thus far several compounds have been identified as SPPARMs, some of which are already in clinical testing (Table 3) (122–125). The focus of SPPARM research is PPAR, because the control of adverse effects of PPAR could contribute greatly to improve the treatment of diabetes.
Conclusions.
This review highlights the different levels at which the members of the PPAR family affect obesity, diabetes, and cardiovascular disease. The current publication rate on this topic is illustrative of the interest in this field. The combined efforts of basic and clinical science together with pharmaceutical developments resulted in the discovery of many new pathways, treatment strategies, and drugs of potential interest for the treatment of obesity, diabetes, and cardiovascular disease.
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Footnotes
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Supported by a grant from the Fondation Leducq.
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References
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1. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators Nature 1990;347:645-650.[CrossRef][Medline]2. Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists Diabetes 2005;54:2460-2470.[Abstract/Free Full Text] 3. Auwerx J, Schoonjans K, Fruchart JC, Staels B. Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR Atherosclerosis 1996;124(Suppl):S29-S37.[CrossRef][Web of Science][Medline] 4. Mukherjee R, Jow L, Noonan D, McDonnell DP. Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators J Steroid Biochem Mol Biol 1994;51:157-166.[CrossRef][Web of Science][Medline] 5. Auboeuf D, Rieusset J, Fajas L, et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients Diabetes 1997;46:1319-1327.[Abstract] 6. Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne B. Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding Endocrinology 2001;142:4195-4202.[Abstract/Free Full Text] 7. Krey G, Braissant O, L'Horset F, et al. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay Mol Endocrinol 1997;11:779-791.[Abstract/Free Full Text] 8. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma Proc Natl Acad Sci U S A 1997;94:4318-4323.[Abstract/Free Full Text] 9. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta Proc Natl Acad Sci U S A 1997;94:4312-4317.[Abstract/Free Full Text] 10. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators Nature 1998;393:790-793.[CrossRef][Medline] 11. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterolVeterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-418.[Abstract/Free Full Text] 12. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial Lancet 2005;366:1849-1861.[CrossRef][Web of Science][Medline] 13. Chinetti-Gbaguidi G, Fruchart JC, Staels B. Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy Curr Opin Pharmacol 2005;5:177-183.[CrossRef][Web of Science][Medline] 14. Prisant LM. Clinical trials and lipid guidelines for type II diabetes J Clin Pharmacol 2004;44:423-430.[Abstract/Free Full Text] 15. FIELD Study Investigators The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [ISRCTN64783481] Cardiovasc Diabetol 2004;3:9.[CrossRef][Medline] 16. DIAS Authors Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study Lancet 2001;357:905-910.[CrossRef][Web of Science][Medline] 17. Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS) Am J Kidney Dis 2005;45:485-493.[CrossRef][Web of Science][Medline] 18. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemiaSafety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245.[Abstract] 19. Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study JAMA 1988;260:641-651.[Abstract/Free Full Text] 20. Bloomfield-Rubins H, Davenport J, Babikian V, et al. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT) Circulation 2001;103:2828-2833.[Abstract/Free Full Text] 21. Frick MH, Syvanne M, Nieminen MS, et al. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterolLopid Coronary Angiography Trial (LOCAT) Study Group. Circulation 1997;96:2137-2143.[Abstract/Free Full Text] 22. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, deFaire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients Lancet 1996;347:849-853.[CrossRef][Web of Science][Medline] 23. Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko V, Behar S. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome Arch Intern Med 2005;165:1154-1160.[Abstract/Free Full Text] 24. Marx N, Duez H, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells Circ Res 2004;94:1168-1178.[Abstract/Free Full Text] 25. Madej A, Okopien B, Kowalski J, et al. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb Int J Clin Pharmacol Ther 1998;36:345-349.[Web of Science][Medline] 26. Ye P, Li JJ, Su G, Zhang C. Effects of fenofibrate on inflammatory cytokines and blood pressure in patients with hypertriglyceridemia Clin Chim Acta 2005;356:229-232.[CrossRef][Web of Science][Medline] 27. Okopien B, Krysiak R, Kowalski J, et al. Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates J Cardiovasc Pharmacol 2005;46:377-386.[CrossRef][Web of Science][Medline] 28. Gizard F, Amant C, Barbier O, et al. PPARalpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16. J Clin Invest 2005;115:3228–38.. 29. deLorgeril M, Salen P, Paillard F, Lacan P, Richard G. Lipid-lowering drugs and homocysteine Lancet 1999;353:209-210.[Web of Science][Medline] 30. Genest J, Frohlich J, Steiner G. Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus Am J Cardiol 2004;93:848-853.[CrossRef][Web of Science][Medline] 31. Mikael LG, Genest J Jr., Rozen R. Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. Circ Res 2006;98:564–71.. 32. Oldemeyer JB, Lund RJ, Koch M, Meares AJ, Dunlay R. Rhabdomyolysis and acute renal failure after changing statin-fibrate combinations Cardiology 2000;94:127-128.[CrossRef][Web of Science][Medline] 33. Kind AH, Zakowski LJ, McBride PE. Rhabdomyolysis from the combination of a statin and gemfibrozil: an uncommon but serious adverse reaction WMJ 2002;101:53-56.[Medline] 34. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin Am J Cardiol 2005;95:120-122.[CrossRef][Web of Science][Medline] 35. Backman JT, Kyrklund C, Neuvonen M, Neuvonen PJ. Gemfibrozil greatly increases plasma concentrations of cerivastatin Clin Pharmacol Ther 2002;72:685-691.[CrossRef][Web of Science][Medline] 36. Davidson MH. Controversy surrounding the safety of cerivastatin Expert Opin Drug Saf 2002;1:207-212.[CrossRef][Medline] 37. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy JAMA 2003;289:1681-1690.[Abstract/Free Full Text] 38. Berger J, Leibowitz, MD, Doebber TW, et al. Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects J Biol Chem 1999;274:6718-6725.[Abstract/Free Full Text] 39. Oliver Jr. WR, Shenk JL, Snaith MR, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport Proc Natl Acad Sci U S A 2001;98:5306-5311.[Abstract/Free Full Text] 40. Leibowitz MD, Fievet C, Hennuyer N, et al. Activation of PPARdelta alters lipid metabolism in db/db mice FEBS Lett 2000;473:333-336.[CrossRef][Web of Science][Medline] 41. Luquet S, Lopez-Soriano J, Holst D, et al. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability FASEB J 2003;17:2299-2301.[Abstract/Free Full Text] 42. Reed KR, Sansom OJ, Hayes AJ, et al. PPARdelta status and Apc-mediated tumourigenesis in the mouse intestine Oncogene 2004;23:8992-8996.[CrossRef][Web of Science][Medline] 43. Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth Nat Med 2004;10:245-247.[CrossRef][Web of Science][Medline] 44. Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ, Peters JM. Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis Nat Med 2004;10:481-483.[CrossRef][Web of Science][Medline] 45. Fukumoto K, Yano Y, Virgona N, et al. Peroxisome proliferator-activated receptor delta as a molecular target to regulate lung cancer cell growth FEBS Lett 2005;579:3829-3836.[CrossRef][Web of Science][Medline] 46. Yin Y, Russell RG, Dettin LE, et al. Peroxisome proliferator-activated receptor delta and gamma agonists differentially alter tumor differentiation and progression during mammary carcinogenesis Cancer Res 2005;65:3950-3957.[Abstract/Free Full Text] 47. Yki-Jarvinen H. Thiazolidinediones N Engl J Med 2004;351:1106-1118.[Free Full Text] 48. Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus Arterioscler Thromb Vasc Biol 2004;24:930-934.[Abstract/Free Full Text] 49. Osman A, Otero J, Brizolara A, et al. Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes Am Heart J 2004;147:e23.[CrossRef][Medline] 50. Choi D, Kim SK, Choi SH, et al. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes Diabetes Care 2004;27:2654-2660.[Abstract/Free Full Text] 51. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Lancet 2005;366:1279-1289.[CrossRef][Web of Science][Medline] 52. Takagi T, Yamamuro A, Tamita K, et al. Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study Am Heart J 2003;146:E5.[CrossRef][Medline] 53. Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia Diabetes Care 2005;28:1547-1554.[Abstract/Free Full Text] 54. Staels B. PPARgamma and atherosclerosis Curr Med Res Opin 2005;21(Suppl 1):S13-S20. 55. Marx N, Froehlich J, Siam L, et al. Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease Arterioscler Thromb Vasc Biol 2003;23:283-288.[Abstract/Free Full Text] 56. Marx N, Imhof A, Froehlich J, et al. Effect of rosiglitazone treatment on soluble CD40L in patients with type 2 diabetes and coronary artery disease Circulation 2003;107:1954-1957.[Abstract/Free Full Text] 57. Pfutzner A, Marx N, Lubben G, et al. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study J Am Coll Cardiol 2005;45:1925-1931.[Abstract/Free Full Text] 58. Sidhu JS, Cowan D, Kaski JC. The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients J Am Coll Cardiol 2003;42:1757-1763.[Abstract/Free Full Text] 59. Corti R, Osende JI, Fallon JT, et al. The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging J Am Coll Cardiol 2004;43:464-473.[Abstract/Free Full Text] 60. Erdmann E. Late Breaking News, AHA. 2005. Available at: http://www.proactive-results.com. Accessed November 2005.. 61. Zhang H, Zhang A, Kohan DE, Nelson RD, Gonzalez FJ, Yang T. Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention Proc Natl Acad Sci U S A 2005;102:9406-9411.[Abstract/Free Full Text] 62. Marceille JR, Goins JA, Soni R, Biery JC, Lee TA. Chronic heart failure-related interventions after starting rosiglitazone in patients receiving insulin Pharmacotherapy 2004;24:1317-1322.[CrossRef][Web of Science][Medline] 63. Scheen AJ. Combined thiazolidinedione-insulin therapy: should we be concerned about safety? Drug Saf 2004;27:841-856.[CrossRef][Web of Science][Medline] 64. Flavell DM, Ireland H, Stephens JW, et al. Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes Diabetes 2005;54:582-586.[Abstract/Free Full Text] 65. Vohl MC, Lepage P, Gaudet D, et al. Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia J Lipid Res 2000;41:945-952.[Abstract/Free Full Text] 66. Evans D, Aberle J, Wendt D, Wolf A, Beisiegel U, Mann WA. A polymorphism, L162V, in the peroxisome proliferator-activated receptor alpha (PPARalpha) gene is associated with lower body mass index in patients with non-insulin-dependent diabetes mellitus J Mol Med 2001;79:198-204.[CrossRef][Web of Science][Medline] 67. Flavell DM, Jamshidi Y, Hawe E, et al. Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease Circulation 2002;105:1440-1445.[Abstract/Free Full Text] 68. Jamshidi Y, Montgomery HE, Hense HW, et al. Peroxisome proliferator-activated receptor alpha gene regulates left ventricular growth in response to exercise and hypertension Circulation 2002;105:950-955.[Abstract/Free Full Text] 69. Flavell DM, Pineda Torra I, Jamshidi Y, et al. Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in type II diabetic subjects Diabetologia 2000;43:673-680.[CrossRef][Web of Science][Medline] 70. Lee SS, Pineau T, Drago J, et al. Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators Mol Cell Biol 1995;15:3012-3022.[Abstract] 71. Finck BN, Bernal-Mizrachi C, Han DH, et al. A potential link between muscle peroxisome proliferator-activated receptor-alpha signaling and obesity-related diabetes Cell Metab 2005;1:133-144.[CrossRef][Web of Science][Medline] 72. Steiner G. Altering triglyceride concentrations changes insulin-glucose relationships in hypertriglyceridemic patientsDouble-blind study with gemfibrozil with implications for atherosclerosis. Diabetes Care 1991;14:1077-1081.[Abstract] 73. Guerre-Millo M, Gervois P, Raspe E, et al. Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity J Biol Chem 2000;275:16638-16642.[Abstract/Free Full Text] 74. Skogsberg J, Kannisto K, Cassel TN, Hamsten A, Eriksson P, Ehrenborg E. Evidence that peroxisome proliferator-activated receptor delta influences cholesterol metabolism in men Arterioscler Thromb Vasc Biol 2003;23:637-643.[Abstract/Free Full Text] 75. Shin HD, Park BL, Kim LH, et al. Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity Diabetes 2004;53:847-851.[Abstract/Free Full Text] 76. Haslam DW, James WP. Obesity Lancet 2005;366:1197-1209.[CrossRef][Web of Science][Medline] 77. Peters JM, Lee SS, Li W, et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta) Mol Cell Biol 2000;20:5119-5128.[Abstract/Free Full Text] 78. Wang YX, Lee CH, Tiep S, et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity Cell 2003;113:159-170.[CrossRef][Web of Science][Medline] 79. Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma J Clin Invest 2004;114:1564-1576.[CrossRef][Web of Science][Medline] 80. Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity Nat Genet 1998;20:284-287.[CrossRef][Web of Science][Medline] 81. Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes Nat Genet 2000;26:76-80.[CrossRef][Web of Science][Medline] 82. Yliharsila H, Eriksson JG, Forsen T, et al. Interactions between peroxisome proliferator-activated receptor-gamma 2 gene polymorphisms and size at birth on blood pressure and the use of antihypertensive medication J Hypertens 2004;22:1283-1287.[CrossRef][Web of Science][Medline] 83. Adamo KB, Sigal RJ, Williams K, Kenny G, Prud'homme D, Tesson F. Influence of Pro(12)Ala peroxisome proliferator-activated receptor gamma2 polymorphism on glucose response to exercise training in type 2 diabetes Diabetologia 2005;48:1503-1509.[CrossRef][Web of Science][Medline] 84. Wang XL, Oosterhof J, Duarte N. Peroxisome proliferator-activated receptor gamma C161–>T polymorphism and coronary artery disease Cardiovasc Res 1999;44:588-594.[Abstract/Free Full Text] 85. Tavares V, Hirata RD, Rodrigues AC, et al. Effect of the per-oxisome proliferator-activated receptor-gamma C161T polymorphism on lipid profile in Brazilian patients with type 2 diabetes mellitus J Endocrinol Invest 2005;28:129-136.[Web of Science][Medline] 86. Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation N Engl J Med 1998;339:953-959.[Abstract/Free Full Text] 87. Savage DB, Tan GD, Acerini CL, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma Diabetes 2003;52:910-917.[Abstract/Free Full Text] 88. Barroso I, Gurnell M, Crowley VE, et al. Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension Nature 1999;402:880-883.[Medline] 89. Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy J Clin Endocrinol Metab 2002;87:408-411.[Abstract/Free Full Text] 90. Meirhaeghe A, Cottel D, Amouyel P, Dallongeville J. Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women Diabetes 2005;54:3043-3048.[Abstract/Free Full Text] 91. Hamann A, Munzberg H, Buttron P, et al. Missense variants in the human peroxisome proliferator-activated receptor-gamma2 gene in lean and obese subjects Eur J Endocrinol 1999;141:90-92.[Abstract] 92. Schaffler A, Barth N, Schmitz G, Zietz B, Palitzsch KD, Scholmerich J. Frequency and significance of pro12Ala and pro115Gln polymorphism in gene for peroxisome proliferation-activated receptor-gamma regarding metabolic parameters in a Caucasian cohort Endocrine 2001;14:369-373.[CrossRef][Web of Science][Medline] 93. Bluher M, Paschke R. Analysis of the relationship between PPAR-gamma 2 gene variants and severe insulin resistance in obese patients with impaired glucose tolerance Exp Clin Endocrinol Diabetes 2003;111:85-90.[CrossRef][Web of Science][Medline] 94. Barak Y, Nelson MC, Ong ES, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development Mol Cell 1999;4:585-595.[CrossRef][Web of Science][Medline] 95. Miles PD, Barak Y, Evans RM, Olefsky JM. Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding Am J Physiol Endocrinol Metab 2003;284:E618-E626.[Abstract/Free Full Text] 96. Hevener AL, He W, Barak Y, et al. Muscle-specific Pparg deletion causes insulin resistance Nat Med 2003;9:1491-1497.[CrossRef][Web of Science][Medline] 97. Norris AW, Chen L, Fisher SJ, et al. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones J Clin Invest 2003;112:608-618.[CrossRef][Web of Science][Medline] 98. Jones JR, Barrick C, Kim KA, et al. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance Proc Natl Acad Sci U S A 2005;102:6207-6212.[Abstract/Free Full Text] 99. He W, Barak Y, Hevener A, et al. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle Proc Natl Acad Sci U S A 2003;100:15712-15717.[Abstract/Free Full Text] 100. Zhang FF, Cui T, Xiong C, et al. Selective disruption of PPARgamma2 impairs the development of adipose tissue and insulin sensitivity Proc Natl Acad Sci U S A 2004;101:10703-10708.[Abstract/Free Full Text] 101. Koutnikova H, Cock TA, Watanabe M, et al. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice Proc Natl Acad Sci U S A 2003;100:14457-14462.[Abstract/Free Full Text] 102. Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus J Clin Invest 2002;109:121-130.[CrossRef][Web of Science][Medline] 103. Sambandam N, Morabito D, Wagg C, Finck BN, Kelly DP, Lopaschuk GD. Chronic activation of PPAR(alpha) is detrimental to cardiac recovery following ischemia. Am J Physiol Heart Circ Physiol 2005;290:H87–95.. 104. Wayman NS, Ellis BL, Thiemermann C. Ligands of the peroxisome proliferator-activated receptor-PPAR-a reduce myocardial infarct size Med Sci Monit 2002;8:BR243-BR247.[Medline] 105. Yue TL, Bao W, Jucker BM, et al. Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury Circulation 2003;108:2393-2399.[Abstract/Free Full Text] 106. Ogata T, Miyauchi T, Sakai S, Irukayama-Tomobe Y, Goto K, Yamaguchi I. Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts Clin Sci (Lond) 2002;103(Suppl 48):284S-288S.[Medline] 107. Diep QN, Benkirane K, Amiri F, Cohn JS, Endemann D, Schiffrin EL. PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats J Mol Cell Cardiol 2004;36:295-304.[CrossRef][Web of Science][Medline] 108. Liang F, Wang F, Zhang S, Gardner DG. Peroxisome proliferator activated receptor (PPAR)alpha agonists inhibit hypertrophy of neonatal rat cardiac myocytes Endocrinology 2003;144:4187-4194.[Abstract/Free Full Text] 109. Gomez-Garre D, Herraiz M, Gonzalez-Rubio ML, et al. Activation of peroxisome proliferator-activated receptor-alpha and -gamma in auricular tissue from heart failure patients. Eur J Heart Fail 2006;8:154–61.. 110. Cheng L, Ding G, Qin Q, et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy Nat Med 2004;10:1245-1250.[CrossRef][Web of Science][Medline] 111. Duan SZ, Ivashchenko CY, Russell MW, Milstone DS, Mortensen RM. Cardiomyocyte-specific knockout and agonist of peroxisome proliferator-activated receptor-gamma both induce cardiac hypertrophy in mice Circ Res 2005;97:372-379.[Abstract/Free Full Text] 112. Khandoudi N, Delerive P, Berrebi-Bertrand I, Buckingham RE, Staels B, Bril A. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury Diabetes 2002;51:1507-1514.[Abstract/Free Full Text] 113. Wayman NS, Hattori Y, McDonald MC, et al. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size FASEB J 2002;16:1027-1040.[Abstract/Free Full Text] 114. Hegarty BD, Furler SM, Oakes ND, Kraegen EW, Cooney GJ. Peroxisome proliferator-activated receptor (PPAR) activation induces tissue-specific effects on fatty acid uptake and metabolism in vivo—a study using the novel PPARalpha/gamma agonist tesaglitazar Endocrinology 2004;145:3158-3164.[Abstract/Free Full Text] 115. Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm Diabetes Care 2004;27:1324-1329.[Abstract/Free Full Text] 116. Buse JB, Rubin CJ, Frederich R, et al. Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes Clin Ther 2005;27:1181-1195.[CrossRef][Web of Science][Medline] 117. Nissen SE, Wolski K, Topol EJ. Effect of Muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581–6.. 118. Liu KG, Lambert MH, Leesnitzer LM, et al. Identification of a series of PPAR gamma/delta dual agonists via solid-phase parallel synthesis Bioorg Med Chem Lett 2001;11:2959-2962.[CrossRef][Medline] 119. Wallace JM, Schwarz M, Coward P, et al. Effects of peroxisome proliferator-activated receptor alpha/delta agonists on HDL-cholesterol in vervet monkeys J Lipid Res 2005;46:1009-1016.[Abstract/Free Full Text] 120. Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons Cardiovasc Diabetol 2005;4:14.[CrossRef][Medline] 121. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease Trends Pharmacol Sci 2005;26:244-251.[CrossRef][Medline] 122. Misra P, Chakrabarti R, Vikramadithyan RK, et al. PAT5A: a partial agonist of peroxisome proliferator-activated receptor gamma is a potent antidiabetic thiazolidinedione yet weakly adipogenic J Pharmacol Exp Ther 2003;306:763-771.[Abstract/Free Full Text] 123. Bruemmer D, Berger JP, Liu J, et al. A non-thiazolidinedione partial peroxisome proliferator-activated receptor gamma ligand inhibits vascular smooth muscle cell growth Eur J Pharmacol 2003;466:225-234.[CrossRef][Web of Science][Medline] 124. Minoura H, Takeshita S, Yamamoto T, et al. Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist, on insulin resistance in Zucker fatty rat. Eur J Pharmacol 2005;519:182–90.. 125. Schupp M, Clemenz M, Gineste R, et al. Molecular characterization of new selective peroxisome proliferator-activated receptor (gamma) modulators with angiotensin receptor blocking activity Diabetes 2005;54:3442-3452.[Abstract/Free Full Text]
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Abstract
Actions of PPAR agonists