This study was designed to investigate the effects of various chemically distinct activators of PPAR‐γ and PPAR‐α 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‐γ (isoform 1 but not isoform 2) as well as PPAR‐β and PPAR‐α 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‐γ (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as wel 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‐α (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‐γ ligand, 15deoxyΔ^12,14‐prostagalndin J₂ (15D‐PGJ₂). The mechanisms of the cardioprotective effects of 15D‐PGJ₂ may include 1) activation of PPAR‐α, 2) activation of PPAR‐γ, 3) expression of HO‐1, and 4) inhibition of the activation of NF‐KB in the ischemic‐reperfused heart. Inhibition by 15D‐PGJ₂ of the activation of NF‐κB 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‐γ and PPAR‐α 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 ischemiareperfusion 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 ischemiareperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D‐PGJ₂, however, are due to the activation of PPAR‐γ. 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‐γ 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‐γ and PPAR‐α) reduce myocardial infarct size. FASEB J. 16, 1027–1040 (2002)