ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-β/δ ATTENUATES MYOCARDIAL ISCHEMIA/REPERFUSION INJURY IN THE RAT


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Abstract

Peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) is a transcription factor that belongs to the PPAR nuclear hormone receptor family. There is little information about the effects of the immediate administration of specific ligands of PPAR-β/δ (e.g., GW0742) in animal models of myocardial I/R injury. Using a rat model of regional myocardial I/R in vivo, we have investigated the effects of immediate administration of GW0742 on myocardial infarct size. Male Wistar rats were subjected to 25 min of regional ischemia followed by 2 h of reperfusion and treated with GW0742 (3, 30, or 300μg/kg i.v. given at 30 min before ischemia and again at the start of reperfusion). Higher doses (30 or 300 μg/kg i.v.) of GW0742 caused a reduction in infarct size, whereas the lowest dose used was not effective. The degree of cardioprotection was similar when GW0742 (30 μg/kg i.v.) was given on reperfusion alone. The reduction in infarct size afforded by GW0742 was not reduced by the competitive irreversible PPAR-α antagonist GW6471 (1 mg/kg i.v., 15 min before ischemia). GW0742 (30 μg/kg i.v.) reduced the I/R-induced (a) decrease in the phosphorylation of Akt and glycogen synthase kinase-3β, (b) nuclear translocation of the p65 subunit of nuclear factor-κB (activation of nuclear factor-κB), and (c) increase in the expression of iNOS and cyclooxygenase-2. Thus, immediate administration of the PPAR-β/δ ligand GW0742 during reperfusion reduces myocardial infarct size in the rat by a mechanism that may involve inhibition of the activity of glycogen synthase kinase-3β secondary to activation of the Akt pathway.

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