Activation of peroxisome proliferator-activated receptor-beta/delta attenuates myocardial ischemia/reperfusion injury in the rat.
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.
Kapoor
Amar
A
Center for Translational Medicine & Therapeutics, Queen Mary University of London, William Harvey Research Institute, London, United Kingdom.
Collino
Massimo
M
Castiglia
Sara
S
Fantozzi
Roberto
R
Thiemermann
Christoph
C
D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000627:therapeutic use*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
D051546:Cyclooxygenase 2; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D052247:Nitric Oxide Synthase Type II; D010080:Oxazoles; D047493:PPAR alpha; D047494:PPAR delta; D048068:PPAR-beta; D051057:Proto-Oncogene Proteins c-akt; D013844:Thiazoles; D014443:Tyrosine; C449302:GW 6471; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C496318:Nos2 protein, rat; C489691:Ptgs2 protein, rat; C000605508:Gsk3b protein, rat