title: Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.
abstract: This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.
authors.affiliation: Department of Experimental Medicine and Nephrology, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London EC1M 6BQ, UK.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Wayman
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Michelle C
authors.initials: MC
authors.lastname: McDonald
authors.forename: Helder
authors.initials: H
authors.lastname: Mota-Filipe
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Babrbara
authors.initials: B
authors.lastname: Pisano
authors.forename: Prabal K
authors.initials: PK
authors.lastname: Chatterjee
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000328:Adult; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D002994:Clofibrate / Q000627:therapeutic use; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology; D051547:Heme Oxygenase-1; D006801:Humans; D008024:Ligands; D008297:Male; D008565:Membrane Proteins; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011454:Prostaglandins A / Q000627:therapeutic use; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000627:therapeutic use; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002316:Cardiotonic Agents; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D008024:Ligands; D008565:Membrane Proteins; D011454:Prostaglandins A; D020033:Protein Isoforms; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C006253:pirinixic acid; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D002994:Clofibrate; D015230:Prostaglandin D2; C039671:ciglitazone; C100573:prostaglandin A1; D000077205:Pioglitazone