Peroxisome proliferator-activated receptor (
PPAR)-delta is a
transcription factor that belongs to the
PPAR family.
PPAR-delta is abundantly expressed in the heart, and its role in the heart is largely unknown. We tested whether pharmacological activation of
PPAR-delta protects the heart from
ischemia/reperfusion (I/R) injury in male Zucker fatty rats, a rodent model of
obesity and
dyslipidemia. A highly selective
PPAR-delta agonist, [4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl] thio]-2-methylphenoxy]
acetic acid (
GW0742), was administered for 7 days
at 10 mg/kg/day (p.o., once a day). Ischemic injury was produced by occlusion of the left anterior descending artery for 30 min followed by reperfusion for up to 24 h. Treatment with
GW0742 reduced serum levels of cardiac
troponin-I and
infarct size by 63% (p < 0.01) and 32% (p < 0.01), respectively, and improved left ventricular function. Treatment with
GW0742 up-regulated gene expression involved in cardiac
fatty acid oxidation, increased fat use in the heart, and reduced serum levels of
free fatty acids. The enhanced cardiac expression of
interleukin (IL)-6,
IL-8,
intercellular adhesion molecule-1, and
monocyte chemoattractant protein-1 induced by I/R were significantly attenuated by
GW0742. Treatment with
GW0742 also reduced apoptotic cardiomyocytes by 34% and cardiac
caspase-3 activity by 61% (both p < 0.01 versus vehicle).
GW0742 differentially regulated Bcl family members, favoring cell survival, and attenuated I/R-induced cardiac mitochondrial damage. In addition,
GW0742 treatment augmented the cardiac Akt signaling pathway, as reflected by enhanced phospho-3-phosphoinositide-dependent kinase-1 and p-Akt. The results indicate that activation of
PPAR-delta protected the heart from I/R injury in Zucker fatty rats, and multiple mechanisms including amelioration of lipotoxicity, anti-
inflammation, and up-regulation of prosurvival signaling contribute together to the cardioprotection.