Activation of peroxisome proliferator-activated receptor-beta/delta 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.

• Authors: Amar Kapoor, Massimo Collino, Sara Castiglia, Roberto Fantozzi, Christoph Thiemermann
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 34 Issue 2 Pg. 117-24 (Aug 2010) ISSN: 1540-0514 [Electronic] United States
• PMID: 19997057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GW 6471
• Oxazoles
• PPAR alpha
• PPAR delta
• PPAR-beta
• Thiazoles
• Tyrosine
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• Nitric Oxide Synthase Type II
• Nos2 protein, rat
• Cyclooxygenase 2
• Ptgs2 protein, rat
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Cyclooxygenase 2 (biosynthesis)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Hemodynamics (drug effects)
• Male
• Myocardial Reperfusion Injury (pathology, prevention & control)
• Myocardium (metabolism)
• Nitric Oxide Synthase Type II (biosynthesis)
• Oxazoles (pharmacology)
• PPAR alpha (antagonists & inhibitors)
• PPAR delta (agonists, metabolism)
• PPAR-beta (agonists, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Wistar
• Thiazoles (therapeutic use)
• Tyrosine (analogs & derivatives, pharmacology)