{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T03:56:21Z","timestamp":1769831781838,"version":"3.49.0"},"reference-count":48,"publisher":"American Diabetes Association","issue":"9","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,9,1]]},"abstract":"<jats:p>OBJECTIVE\u2014Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator\u2013activated receptor \u03b3 (PPAR\u03b3) 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\u03b3 ligands could attenuate cardiac fibrosis.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014Wild-type cardiomyocyte- and macrophage-specific PPAR\u03b3\u2212\/\u2212 mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPAR\u03b3 ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPAR\u03b3 in cardiac fibrosis.<\/jats:p>\n               <jats:p>RESULTS\u2014Cardiomyocyte-specific PPAR\u03b3\u2212\/\u2212 mice (cPPAR\u03b3\u2212\/\u2212) 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\u03b3\u2212\/\u2212 mice but induced hypertrophy in a PPAR\u03b3-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPAR\u03b3\u2013independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPAR\u03b3 ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPAR\u03b3\u2212\/\u2212 mice.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014We arrived at the following conclusions: 1) both cardiomyocyte-specific PPAR\u03b3 deficiency and activation promote cardiac hypertrophy, 2) both cardiomyocyte and monocyte PPAR\u03b3 regulate cardiac macrophage infiltration, 3) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4) macrophage PPAR\u03b3 activation prevents myocardial macrophage accumulation, and 5) PPAR\u03b3 ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.<\/jats:p>","DOI":"10.2337\/db07-0924","type":"journal-article","created":{"date-parts":[[2008,5,30]],"date-time":"2008-05-30T00:13:15Z","timestamp":1212106395000},"page":"2470-2479","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":66,"title":["Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator\u2013Activated Receptor \u03b3 in Cardiac Fibrosis"],"prefix":"10.2337","volume":"57","author":[{"given":"Evren","family":"Caglayan","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California"},{"name":"Klinik III fu\u0308r Innere Medizin, Universita\u0308t zu Ko\u0308ln, Ko\u0308ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bradley","family":"Stauber","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan R.","family":"Collins","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Obesity and Lipids, The Methodist Hospital Research Institute, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Lyon","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Obesity and Lipids, The Methodist Hospital Research Institute, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fen","family":"Yin","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joey","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Obesity and Lipids, The Methodist Hospital Research Institute, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Rosenkranz","sequence":"additional","affiliation":[{"name":"Klinik III fu\u0308r Innere Medizin, Universita\u0308t zu Ko\u0308ln, Ko\u0308ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erland","family":"Erdmann","sequence":"additional","affiliation":[{"name":"Klinik III fu\u0308r Innere Medizin, Universita\u0308t zu Ko\u0308ln, Ko\u0308ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leif E.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Center for Biostatistics, The Methodist Hospital Research Institute, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Ross","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Veterans Affairs Medical Center and University of California, San Diego, San Diego, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajendra K.","family":"Tangirala","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willa A.","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Division of Diabetes, Obesity and Lipids, The Methodist Hospital Research Institute, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","reference":[{"key":"2022031210125002900_R1","doi-asserted-by":"crossref","unstructured":"Asbun J, Villarreal FJ: The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. 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