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

¹ Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
² Klinik III für Innere Medizin, Universität zu Köln, Köln, Germany
³ Division of Diabetes, Obesity and Lipids, The Methodist Hospital Research Institute, Houston, Texas
⁴ Center for Biostatistics, The Methodist Hospital Research Institute, Houston, Texas
⁵ Division of Cardiology, Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, San Diego, California

Corresponding author: Willa A. Hsueh, wahsueh{at}tmhs.org

OBJECTIVE—Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor (PPAR) 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 ligands could attenuate cardiac fibrosis.

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

RESULTS—Cardiomyocyte-specific PPAR^–/– mice (cPPAR^–/–) 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^–/– mice but induced hypertrophy in a PPAR-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPAR–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 ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPAR^–/– mice.

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

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