Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

Abstract

OBJECTIVE—Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis.

RESEARCH DESIGN AND METHODS—Wild-type cardiomyocyte- and macrophage-specific PPARγ^−/− mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARγ ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARγ in cardiac fibrosis.

RESULTS—Cardiomyocyte-specific PPARγ^−/− mice (cPPARγ^−/−) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARγ^−/− mice but induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARγ–independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARγ^−/− mice.

CONCLUSIONS—We arrived at the following conclusions: 1) both cardiomyocyte-specific PPARγ deficiency and activation promote cardiac hypertrophy, 2) both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration, 3) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4) macrophage PPARγ activation prevents myocardial macrophage accumulation, and 5) PPARγ ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.