Ligands of the peroxisome proliferator‐activated receptors (PPAR‐γ and PPAR‐α) reduce myocardial infarct size

Autor: Yoshiyuki Hattori, Babrbara Pisano, Prabal K. Chatterjee, Helder Mota-Filipe, Christoph Thiemermann, Salvatore Cuzzocrea, Michelle C. McDonald, Nicole S. Wayman
Rok vydání: 2002
Předmět:
Male
Chemokine
Myocardial Infarction
Receptors
Cytoplasmic and Nuclear
Peroxisome proliferator-activated receptor
Ligands
Biochemistry
chemistry.chemical_compound
Protein Isoforms
Clofibrate
Receptor
Cells
Cultured
Chemokine CCL2
chemistry.chemical_classification
biology
Prostaglandin D2
Nitrotyrosine
Nitric oxide synthase
Rosiglitazone
Peroxynitrite
Biotechnology
medicine.drug
Adult
medicine.medical_specialty
Cardiotonic Agents
Myocardial Reperfusion Injury
Cell Line
Internal medicine
Ciglitazone
Genetics
medicine
Animals
Humans
RNA
Messenger
Rats
Wistar
Molecular Biology
Prostaglandins A
Pioglitazone
Membrane Proteins
Rats
Thiazoles
Pyrimidines
Endocrinology
chemistry
Heme Oxygenase (Decyclizing)
biology.protein
Thiazolidinediones
Cell Adhesion Molecules
Heme Oxygenase-1
Transcription Factors
Zdroj: The FASEB Journal. 16:1027-1040
ISSN: 1530-6860
0892-6638
Popis: 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.
Databáze: OpenAIRE
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