In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone

Background-Diabetes is associated with increased risk of mortality as a con sequence of acute myocardial infarction. This study determined whether rosi glitazone (ROSI) could reduce myocardial infarction after ischemia/reperfus ion injury. Methods and Results-Male Lewis rats were anesthetized, and the left anterio r descending coronary artery was ligated for 30 minutes. After reperfusion for 24 hours, the ischemic and infarct sizes were determined. ROSI at 1 and 3 mg/kg IV reduced infarct size by 30% and 37%, respectively (P <0.01 vers us vehicle). Pretreatment with ROSI (3 mg (.) kg(-1) (.) d(-1) PO) for 7 da ys also reduced infarct size by 24% (P <0.01). ROSI also improved ischemia/ reperfusion-induced myocardial contractile dysfunction. Left ventricular sy stolic pressure and positive and negative maximal values of the first deriv ative of left ventricular pressure (dP/dt) were significantly improved in R OSI-treated rats. ROSI reduced the accumulation of neutrophils and macropha ges in the ischemic heart by 40% and 43%, respectively (P <0.01). Ischemia/ reperfusion induced upregulation of CD11b/CD18 and downregulation of L-sele ctin on neutrophils and monocytes; these effects were significantly attenua ted in ROSI-treated animals. Likewise, intercellular adhesion molecule-1 ex pression in ischemic hearts was markedly diminished by ROSI, as was the isc hemia/reperfusion-stimulated upregulation of monocyte chemoattractant prote in-1. Conclusions-ROSI reduced myocardial infarction and improved contractile dys function caused by ischemia/reperfusion injury. The cardioprotective effect of ROSI was most likely due to inhibition of the inflammatory response.