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and PPAR-
) reduce myocardial infarct size
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;
* Department of Endocrinology, Dokkyo University School of Medicine, Mibu, Japan;
Laboratory of Pharmacology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal;
Institute of Pharmacology, School of Medicine, University of Messina, Messina 98123, Italy; and
Department of Experimental Pharmacology, University of Naples, Federico 11, Italy
1Correspondence: Department of Experimental Medicine and Nephrology, William Harvey Research Institute, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. E-mail: c.thiemermann{at}mds.qmw.ac.uk
This study was designed to investigate the effects of various chemically distinct activators of PPAR-
and PPAR-
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- (isoform 1 but not isoform 2) as well as PPAR-ß and PPAR- 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- (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- (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- ligand, 15-deoxy
12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-, 2) activation of PPAR-, 3) expression of HO-1, and 4) inhibition of the activation of NF-
B in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-B 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- and PPAR- 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-. 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- reduce the tissue necrosis associated with acute myocardial infarction.—Wayman, N. S., Hattori, Y., McDonald, M. C., Mota-Filipe, H., Cuzzocrea, S., Pisano, B., Chatterjee, P. K., Thiemermann, C. Ligands of the peroxisome proliferator-activated receptors (PPAR- and PPAR-) reduce myocardial infarct size.
Key Words: ischemia-reperfusion • infarction • PPAR • heart • adhesion molecules • inducible nitric oxide synthase • reperfusion injury
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