P eroxisome Proliferator-Activated Receptors at the rossroads of Obesity , Diabetes , and Cardiovascular Disease

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: , / , 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. (J Am Coll Cardiol 2006;48:A24–32) © 2006 by the American College of ublished by Elsevier Inc. doi:10.1016/j.jacc.2006.04.097

[1]  R. Rozen,et al.  Elevated Homocysteine Reduces Apolipoprotein A-I Expression in Hyperhomocysteinemic Mice and in Males With Coronary Artery Disease , 2006, Circulation research.

[2]  D. Gómez-Garre,et al.  Activation of peroxisome proliferator-activated receptor-alpha and -gamma in auricular tissue from heart failure patients. , 2006, European journal of heart failure.

[3]  U. Kintscher,et al.  Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. , 2005, Diabetes.

[4]  P Glasziou,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 , 2005, The Lancet.

[5]  E. Topol,et al.  Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. , 2005, JAMA.

[6]  B. Staels,et al.  PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. , 2005, The Journal of clinical investigation.

[7]  Erland Erdmann,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 , 2005, The Lancet.

[8]  P. Amouyel,et al.  Association between peroxisome proliferator-activated receptor gamma haplotypes and the metabolic syndrome in French men and women. , 2005, Diabetes.

[9]  A. Tenenbaum,et al.  Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons , 2005, Cardiovascular Diabetology.

[10]  I. Kawamura,et al.  Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor gamma agonist, on insulin resistance in Zucker fatty rat. , 2005, European journal of pharmacology.

[11]  Robert Krysiak,et al.  Monocyte Release of Tumor Necrosis Factor-α and Interleukin-1β in Primary Type IIa and IIb Dyslipidemic Patients Treated With Statins or Fibrates , 2005, Journal of cardiovascular pharmacology.

[12]  M. Russell,et al.  Cardiomyocyte-Specific Knockout and Agonist of Peroxisome Proliferator–Activated Receptor-γ Both Induce Cardiac Hypertrophy in Mice , 2005, Circulation research.

[13]  B. Staels,et al.  Therapeutic roles of peroxisome proliferator-activated receptor agonists. , 2005, Diabetes.

[14]  R. Sigal,et al.  Influence of Pro12Ala peroxisome proliferator-activated receptor γ2 polymorphism on glucose response to exercise training in type 2 diabetes , 2005, Diabetologia.

[15]  D. Kohan,et al.  Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Nikolaus Marx,et al.  Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. , 2005, Journal of the American College of Cardiology.

[17]  C. Zhang,et al.  Effects of fenofibrate on inflammatory cytokines and blood pressure in patients with hypertriglyceridemia. , 2005, Clinica chimica acta; international journal of clinical chemistry.

[18]  D. Tanné,et al.  Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. , 2005, Archives of internal medicine.

[19]  J. Berger,et al.  PPARs: therapeutic targets for metabolic disease. , 2005, Trends in pharmacological sciences.

[20]  P. Coward,et al.  Effects of peroxisome proliferator-activated receptor α/δ agonists on HDL-cholesterol in vervet monkeys Published, JLR Papers in Press, February 16, 2005. DOI 10.1194/jlr.M500002-JLR200 , 2005, Journal of Lipid Research.

[21]  Alfonso T. Perez,et al.  A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. , 2005, Diabetes care.

[22]  B. Staels,et al.  Role of the PPAR family of nuclear receptors in the regulation of metabolic and cardiovascular homeostasis: new approaches to therapy. , 2005, Current opinion in pharmacology.

[23]  M. Taskinen,et al.  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). , 2005, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[24]  J. Holloszy,et al.  A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes. , 2005, Cell metabolism.

[25]  M. Hirata,et al.  Effect of the peroxisome proliferator-activated receptor-γ C161T polymorphism on lipid profile in Brazilian patients with Type 2 diabetes mellitus , 2005, Journal of endocrinological investigation.

[26]  Y. Yano,et al.  Peroxisome proliferator-activated receptor delta as a molecular target to regulate lung cancer cell growth. , 2005, FEBS letters.

[27]  R. Glazer,et al.  Peroxisome proliferator-activated receptor delta and gamma agonists differentially alter tumor differentiation and progression during mammary carcinogenesis. , 2005, Cancer research.

[28]  M. Davidson,et al.  Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. , 2005, The American journal of cardiology.

[29]  S. Humphries,et al.  Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes. , 2005, Diabetes.

[30]  B Staels,et al.  PPARgamma and atherosclerosis. , 2005, Current medical research and opinion.

[31]  R. Kesterson,et al.  Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Buse,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. , 2005, Clinical therapeutics.

[33]  Y. Jang,et al.  Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. , 2004, Diabetes care.

[34]  Michael D. Schneider,et al.  Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy , 2004, Nature Medicine.

[35]  Jennifer R. Marceille,et al.  Chronic Heart Failure–Related Interventions After Starting Rosiglitazone in Patients Receiving Insulin , 2004, Pharmacotherapy.

[36]  M. Laakso,et al.  Interactions between peroxisome proliferator-activated receptor-γ2 gene polymorphisms and size at birth on blood pressure and the use of antihypertensive medication , 2004, Journal of hypertension.

[37]  M. Saad,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. , 2004, Diabetes care.

[38]  N. Marx,et al.  Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. , 2004, Circulation research.

[39]  P. Fitzgerald,et al.  Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes. , 2004, American heart journal.

[40]  H. Markus,et al.  Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[41]  J. Frohlich,et al.  Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus. , 2004, The American journal of cardiology.

[42]  L. Prisant,et al.  Clinical Trials and Lipid Guidelines for Type II Diabetes , 2004, Journal of clinical pharmacology.

[43]  Rajnish A. Gupta,et al.  Activation of nuclear hormone receptor peroxisome proliferator–activated receptor-δ accelerates intestinal adenoma growth , 2004, Nature Medicine.

[44]  V. Fuster,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. , 2004, Journal of the American College of Cardiology.

[45]  E. Schiffrin,et al.  PPAR alpha activator fenofibrate inhibits myocardial inflammation and fibrosis in angiotensin II-infused rats. , 2004, Journal of molecular and cellular cardiology.

[46]  H. Shin,et al.  Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity. , 2004, Diabetes.

[47]  J. Ward,et al.  Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. , 2004, Nature medicine.

[48]  O. Sansom,et al.  PPARdelta status and Apc-mediated tumourigenesis in the mouse intestine. , 2004, Oncogene.

[49]  Roger A. Davis,et al.  Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. , 2004, The Journal of clinical investigation.

[50]  A. Scheen Combined Thiazolidinedione-Insulin Therapy , 2004, Drug safety.

[51]  M. Fu,et al.  Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  G. Cooney,et al.  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. , 2004, Endocrinology.

[53]  Weimin He,et al.  Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Weimin He,et al.  Muscle-specific Pparg deletion causes insulin resistance , 2003, Nature Medicine.

[55]  J. Kaski,et al.  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. , 2003, Journal of the American College of Cardiology.

[56]  J. Auwerx,et al.  Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPARγ hypomorphic mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[57]  W. Bao,et al.  Activation of Peroxisome Proliferator–Activated Receptor-&agr; Protects the Heart From Ischemia/Reperfusion Injury , 2003, Circulation.

[58]  B. Spiegelman,et al.  Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. , 2003, The Journal of clinical investigation.

[59]  J. Reddy,et al.  PAT5A: A Partial Agonist of Peroxisome Proliferator-Activated Receptor γ Is a Potent Antidiabetic Thiazolidinedione Yet Weakly Adipogenic , 2003, Journal of Pharmacology and Experimental Therapeutics.

[60]  K. Tanabe,et al.  Pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. , 2003, American heart journal.

[61]  W. Koenig,et al.  Effect of Rosiglitazone Treatment on Soluble CD40L in Patients With Type 2 Diabetes and Coronary Artery Disease , 2003, Circulation.

[62]  E. Fleck,et al.  A non-thiazolidinedione partial peroxisome proliferator-activated receptor gamma ligand inhibits vascular smooth muscle cell growth. , 2003, European journal of pharmacology.

[63]  P. Thompson,et al.  Statin-associated myopathy. , 2003, JAMA.

[64]  Jimmy D Bell,et al.  Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. , 2003, Diabetes.

[65]  A. Hamsten,et al.  Evidence That Peroxisome Proliferator–Activated Receptor Delta Influences Cholesterol Metabolism in Men , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[66]  R. Evans,et al.  Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. , 2003, Cell.

[67]  R. Evans,et al.  Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding. , 2003, American journal of physiology. Endocrinology and metabolism.

[68]  W. Koenig,et al.  Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[69]  D. Gardner,et al.  Peroxisome proliferator activated receptor (PPAR)alpha agonists inhibit hypertrophy of neonatal rat cardiac myocytes. , 2003, Endocrinology.

[70]  P. Neuvonen,et al.  Gemfibrozil greatly increases plasma concentrations of cerivastatin , 2002, Clinical pharmacology and therapeutics.

[71]  M. Davidson Controversy surrounding the safety of cerivastatin , 2002, Expert opinion on drug safety.

[72]  I. Yamaguchi,et al.  Stimulation of peroxisome-proliferator-activated receptor alpha (PPAR alpha) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts. , 2002, Clinical science.

[73]  C. Thiemermann,et al.  Ligands of the peroxisome proliferator-activated receptor-PPAR-a reduce myocardial infarct size. , 2002, Medical science monitor : international medical journal of experimental and clinical research.

[74]  S. Cuzzocrea,et al.  Ligands of the peroxisome proliferator‐activated receptors (PPAR‐γ and PPAR‐α) reduce myocardial infarct size , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[75]  B. Staels,et al.  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. , 2002, Diabetes.

[76]  M. Nieminen,et al.  Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. , 2002, Circulation.

[77]  H. Hense,et al.  Peroxisome Proliferator–Activated Receptor &agr; Gene Regulates Left Ventricular Growth in Response to Exercise and Hypertension , 2002, Circulation.

[78]  A. Garg,et al.  A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. , 2002, The Journal of clinical endocrinology and metabolism.

[79]  P. McBride,et al.  Rhabdomyolysis from the combination of a statin and gemfibrozil: an uncommon but serious adverse reaction. , 2002, WMJ : official publication of the State Medical Society of Wisconsin.

[80]  Xianlin Han,et al.  The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. , 2002, The Journal of clinical investigation.

[81]  I. Hamilton-Craig,et al.  Statin‐associated myopathy , 2001, The Medical journal of Australia.

[82]  L. Brass,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) , 2001, Circulation.

[83]  S. Kliewer,et al.  A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[84]  Diabetes Atherosclerosis Intervention Study Investigators Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study , 2001, The Lancet.

[85]  W. Wahli,et al.  Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. , 2001, Endocrinology.

[86]  T. Willson,et al.  Identification of a series of PPAR gamma/delta dual agonists via solid-phase parallel synthesis. , 2001, Bioorganic & medicinal chemistry letters.

[87]  J. Schölmerich,et al.  Frequency and significance of Pro12Ala and Pro115Gln polymorphism in gene for peroxisome proliferation-activated receptor-gamma regarding metabolic parameters in a Caucasian cohort. , 2001, Endocrine.

[88]  R. Dunlay,et al.  Rhabdomyolysis and Acute Renal Failure after Changing Statin-Fibrate Combinations , 2001, Cardiology.

[89]  任艳,et al.  胰岛素增敏剂一Thiazolidinediones研究现状 , 2000 .

[90]  J. Ward,et al.  Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ) , 2000, Molecular and Cellular Biology.

[91]  Bruno Derudas,et al.  Peroxisome Proliferator-activated Receptor α Activators Improve Insulin Sensitivity and Reduce Adiposity* , 2000, The Journal of Biological Chemistry.

[92]  T. Hudson,et al.  Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia. , 2000, Journal of lipid research.

[93]  P. Talmud,et al.  Variation in the PPARα gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects , 2000, Diabetologia.

[94]  J. Auwerx,et al.  Activation of PPARdelta alters lipid metabolism in db/db mice. , 2000, FEBS letters.

[95]  E S Lander,et al.  The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. , 2000, Nature genetics.

[96]  S. O’Rahilly,et al.  Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension , 1999, Nature.

[97]  T. Wilt,et al.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. , 1999, The New England journal of medicine.

[98]  H. Münzberg,et al.  Missense variants in the human peroxisome proliferator-activated receptor-gamma2 gene in lean and obese subjects. , 1999, European journal of endocrinology.

[99]  Margaret S. Wu,et al.  Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects* , 1999, The Journal of Biological Chemistry.

[100]  F. Paillard,et al.  Lipid-lowering drugs and homocysteine , 1999, The Lancet.

[101]  R. Evans,et al.  PPAR gamma is required for placental, cardiac, and adipose tissue development. , 1999, Molecular cell.

[102]  X. L. Wang,et al.  Peroxisome proliferator-activated receptor gamma C161-->T polymorphism and coronary artery disease. , 1999, Cardiovascular research.

[103]  Johan Auwerx,et al.  A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity , 1998, Nature Genetics.

[104]  A. Pfeiffer,et al.  Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. , 1998, The New England journal of medicine.

[105]  B. Okopień,et al.  Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb. , 1998, International journal of clinical pharmacology and therapeutics.

[106]  W. Koenig,et al.  Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. , 1998, Nature.

[107]  M. Nieminen,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 cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. , 1997, Circulation.

[108]  J. Auwerx,et al.  Tissue Distribution and Quantification of the Expression of mRNAs of Peroxisome Proliferator–Activated Receptors and Liver X Receptor-α in Humans: No Alteration in Adipose Tissue of Obese and NIDDM Patients , 1997, Diabetes.

[109]  W. Wahli,et al.  Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. , 1997, Molecular endocrinology.

[110]  J. Lehmann,et al.  Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[111]  Jasmine Chen,et al.  Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[112]  J. Auwerx,et al.  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. , 1996, Atherosclerosis.

[113]  A. Hamsten,et al.  Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients , 1996, The Lancet.

[114]  T. Pineau,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 , 1995, Molecular and cellular biology.

[115]  D. Noonan,et al.  Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators , 1994, The Journal of Steroid Biochemistry and Molecular Biology.

[116]  G. Steiner Altering Triglyceride Concentrations Changes Insulin-Glucose Relationships in Hypertriglyceridemic Patients: Double-Blind Study With Gemfibrozil With Implications for Atherosclerosis , 1991, Diabetes Care.

[117]  I. Issemann,et al.  Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators , 1990, Nature.

[118]  J. Huttunen,et al.  Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. , 1988, JAMA.

[119]  J. Huttunen,et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. , 1987, The New England journal of medicine.