We investigated whether endogenous
ligands of
peroxisome proliferator-activated receptor-gamma (
PPAR-gamma) protect the heart against
ischemia-reperfusion (I/R) injury. The selective
PPAR-gamma antagonist
GW9662 (2-chloro-5-nitrobenzanilide) was used in rat models of 1) regional myocardial I/R, 2) ischemic preconditioning, and 3) delayed cardioprotection by
endotoxin. We also investigated the effects of the selective
cyclooxygenase-2 inhibitor,
parecoxib, on ischemic preconditioning and delayed cardioprotective effects of
endotoxin. Male Wistar rats were anesthetized with
sodium thiopentone. Animals were subjected to either 15 or 25 min of regional myocardial I/R and pretreated with the
PPAR-gamma agonist ciglitazone (0.3 mg/kg), the
PPAR-gamma antagonist
GW9662 (1 mg/kg), or
GW9662 and
ciglitazone. Animals were also subjected to either 1) ischemic preconditioning alone, ischemic preconditioning, and pretreated with either
GW9662 or
parecoxib (20 mg/kg) or 2)
lipopolysaccharide (LPS) (1 mg/kg) alone, LPS, and pretreated with
ciglitazone,
GW9662, or
parecoxib (20 mg/kg).
Myocardial infarct size was determined by p-
nitroblue tetrazolium staining. The
PPAR-gamma antagonist
GW9662 (1 mg/kg) abolished the cardioprotection afforded by the potent
PPAR-gamma agonist ciglitazone (0.3 mg/kg). Neither
GW9662 nor
parecoxib affected the cardioprotective effects of ischemic preconditioning. Pretreatment with
ciglitazone did not provide additional cardioprotection to LPS-treated animals. Both
GW9662 and
parecoxib abolished the delayed cardioprotective effects of
endotoxin. Thus, we propose that 1) endogenous
ligands of
PPAR-gamma are being generated by
myocardial ischemia in sufficient amounts to attenuate myocardial I/R injury, and 2) that
cyclooxygenase-2 metabolites contribute to (or even account for) the cardioprotective effects of
endotoxin (second window of protection) by acting as endogenous
PPAR-gamma ligands.