Activation of peroxisome proliferator-activated receptor-beta/delta attenuates myocardial ischemia/reperfusion injury in the rat

Shock. 2010 Aug;34(2):117-24. doi: 10.1097/SHK.0b013e3181cd86d6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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