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.