Differential roles of cardiomyocyte and macrophage peroxisome proliferator-activated receptor γ in cardiac fibrosis

OBJECTIVE-Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPAR gamma ligands could attenuate cardiac fibrosis. RESEARCH DESIGN AND METHODS-Wild-type cardiomyocyte- and macrophage-specific PPAR gamma(-/-) mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPAR gamma ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPAR gamma in cardiac fibrosis. RESULTS-Cardiomyocyte-specific PPAR gamma(-/-) mice (cPPAR gamma(-/-)) 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 cPPAR gamma(-/-) mice but induced hypertrophy in a PPAR gamma-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPAR gamma-independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPAR gamma ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPAR gamma(-/-) mice. CONCLUSIONS-We arrived at the following conclusions: 1) both cardiomyocyte-specific PPAR gamma deficiency and activation promote cardiac hypertrophy, 2) both cardiomyocyte and monocyte PPAR gamma regulate cardiac macrophage infiltration, 3) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4) macrophage PPAR gamma activation prevents myocardial macrophage accumulation, and 5) PPAR gamma ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration.