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

Abstract

Peroxisome proliferator-activated receptor-beta/delta (PPAR-beta/delta) 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-beta/delta (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 300microg/kg i.v. given at 30 min before ischemia and again at the start of reperfusion). Higher doses (30 or 300 microg/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 microg/kg i.v.) was given on reperfusion alone. The reduction in infarct size afforded by GW0742 was not reduced by the competitive irreversible PPAR-alpha antagonist GW6471 (1 mg/kg i.v., 15 min before ischemia). GW0742 (30 microg/kg i.v.) reduced the I/R-induced (a) decrease in the phosphorylation of Akt and glycogen synthase kinase-3beta, (b) nuclear translocation of the p65 subunit of nuclear factor-kappaB (activation of nuclear factor-kappaB), and (c) increase in the expression of iNOS and cyclooxygenase-2. Thus, immediate administration of the PPAR-beta/delta 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-3beta secondary to activation of the Akt pathway.

Evidence for the Role of Peroxisome Proliferator-Activated Receptor-β/δ in the Development of Spinal Cord Injury

“…The present results, showing an attenuation of SCIinduced up-regulation of TNF-␣ and iNOS by GW0742 are in good agreement with these previous reports showing antiinflammatory effects of PPAR-␤/␦ agonist. These effects could be mediated through regulation of the NF-B pathway, as it had been proposed previously (Kapoor et al, 2009).…”

“…The dose of GW0742 (0.3 mg kg Ϫ1 ) used here was based on a previous dose-response study in a myocardial ischemia and reperfusion study (Kapoor et al, 2009). GW0742 has an EC 50 value of 1 nM compared with 1 and 2 mM for PPAR-␣ and PPAR-␥, respectively.…”

Vitamin D Receptor Activation Protects Against Myocardial Reperfusion Injury Through Inhibition of Apoptosis and Modulation of Autophagy

“…The peroxisome proliferator-activated receptors (PPARa, b, and c) (8,18,26), liver X receptors (22,29), thyroid hormone receptor (46), estrogen receptors (30), androgen receptors (57), and glucocorticoid receptor (25) have been proposed as the endogenous cardioprotective receptors against MI/R injury, while farnesoid-X-receptor (52), mineralocorticoid receptors (32,54), and Nur77 (12) exacerbate MI/R-induced myocardial injury. Our study adds novel evidence that VDR acts as an endogenous cardioprotective nuclear receptor against MI/R injury.…”

The Role of PPARβ/δ in the Management of Metabolic Syndrome and its Associated Cardiovascular Complications

“…Leukocyte infiltration and the related release of proinflammatory cytokines are known to significantly contribute to the tissue injury evoked by reperfusion of ischemic organs and events of organ-related ischemia/reperfusion (I/R) injury, such as myocardial and cerebral infarction, are among the most critical cardiovascular complications evoked by metabolic disorders. We and others have demonstrated that ligand activation of PPAR / evoke organ protection in experimental models of myocardial, renal, intestinal and lung I/R injury by disrupting multiple levels of the inflammatory cascade [88][89][90][91][92]. Similarly, selective PPAR / genetic deletion has been demonstrated to result in both increased kidney dysfunction and brain infarction in mice [91,93].…”