Effect of Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Agonist, on Ischemia-Reperfusion Injury in Rats

Abstract

Two groups of rats were used to examine the effect of pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, on rat hearts using an in vivo model of ischemia-reperfusion (I/R) to elucidate potential mechanisms. One group was the 30-min reperfusion group, which was further subdivided into sham (n = 5), vehicle (n = 6) and pioglitazone (3 mg·kg^–1, n = 7) treatment groups with 30 min ischemia followed by 30 min reperfusion to detect data related to cardiac function and the area of myocardial infarction. The other group was the 120-min reperfusion group, subdivided into sham (n = 5), vehicle (n = 6), and pioglitazone 0.3 mg·kg^–1 (n = 6), 1 mg·kg^–1 (n = 7) and 3 mg·kg^–1 (n = 6) treatment groups. Immunohistochemistry, in situ hybridization, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and DNA agarose gel electrophoresis were performed to detect apoptosis and expressions of Bax, Bcl-2, caspase 3, MMP-2 and PPARγ protein, and MMP-2 and PPARγ mRNA. We found that, after acute treatment with pioglitazone, the ratio of necrosis to area at risk decreased by 28% (p < 0.01) and that of necrosis to left ventricle was reduced by 32% (p < 0.01), compared with the vehicle group. Heart rate and +dp/dt_max, representing the cardiac systolic function, as well as –dp/dt_max, the indicator of cardiac diastolic function, improved significantly at 1 and 30 min after reperfusion (p < 0.05–0.01). Furthermore, myocardial apoptosis was significantly suppressed by acute treatment with pioglitazone as evidenced by the decreased number of TUNEL-positive myocytes and DNA ladder, enhanced Bcl-2 protein expression, reduced Bax and caspase 3 protein expression in a dose-dependent manner compared with vehicle-treated rats. In addition, acute treatment with pioglitazone dose-dependently increased PPARγ expression and decreased MMP-2 expression at protein and mRNA levels. Our findings demonstrate that a PPARγ agonist may protect the heart from I/R injury. The protective effect is likely to occur by reducing cardiomyocyte apoptosis and inhibiting MMP-2.