Pioglitazone, a Peroxisome Proliferator–Activated Receptor-γ Agonist, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction

Abstract

Background— Peroxisome proliferator–activated receptor-γ activators have recently been implicated as regulators of cellular proliferation and inflammatory response such as cytokine expression. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of pioglitazone treatment in an experimental model of chronic heart failure. Methods and Results— Mice with extensive anterior MI were treated with placebo or pioglitazone (3 mg · kg ⁻¹ · d ⁻¹ ) as a dietary supplement for 4 weeks starting 6 hours after surgery. Infarct size and glucose levels were similar among all groups. LV cavity dilatation and dysfunction by echocardiography were significantly attenuated in MI mice given pioglitazone. LV end-diastolic pressure was increased in MI mice and was significantly reduced by pioglitazone treatment. Pioglitazone partially normalized LV dP/dt _max and dP/dt _min , indices of LV contractile function, which were significantly reduced in MI mice. Improvement of LV function by pioglitazone was accompanied by a decrease in myocyte hypertrophy and interstitial fibrosis and a reduced expression of tumor necrosis factor-α, transforming growth factor-β, and monocyte chemoattractant protein-1 genes in the noninfarcted LV from MI mice. LV inducible nitric oxide synthase and gelatinase B protein levels were increased in MI and were not altered by pioglitazone treatment. Conclusions— Pioglitazone improved LV remodeling and function in mice with post-MI heart failure. This effect was associated with an attenuated LV expression of inflammatory cytokines and chemokines. Peroxisome proliferator–activated receptor-γ ligands have promise as preventive and therapeutic agents against heart failure.