Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates myocardial ischernia/reperfusion injury in a rat model

Thiazolidinediones are insulin-sensitizing drugs, ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which play an important role in the modulation of inflammatory responses. Myocardial ischemia/reperfusion (MI/R) injury is associated with inflammation, in which various cells, particularly monocytes and macrophages, are involved. This study examined the effects of the thiazolidinedione peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, in a rat model of MI/R injury. Pioglitazone at 3 mg/kg/day or the vehicle was administered for 7 days before rats were subjected to 30 minutes of coronary ligation followed by 24 hours of reperfusion. The mRNA expression [monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1] in the ischemic region, the number of infiltrating macrophages in the ischemic region, and the myocardial infarct size were examined. The inhibitory effects of pioglitazone on activated macrophages were studied in vitro. Phorbol 12-myristate 13-acetate-induced MCP-1 production, in the absence or presence of pioglitazone, were assayed in cultured macrophages. Compared with the control group, (1) mRNA levels of MCP-1 and intercellular adhesion molecule-1 and the number of infiltrating macrophages in the ischemic region were significantly lower in the pioglitazone-treated group; and (2) myocardial infarct size was significantly smaller in the pioglitazone-treated group. Phorbol 12-myristate 13-acetate-stimulated cultured macrophages in the presence of pioglitazone produced significantly lower levels of MCP-1 than the stimulated control in the absence of pioglitazone. These observations demonstrate that pioglitazone has anti-inflammatory effects in MI/R injury that are independent of its insulin-sensitizing effect.