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Integrated Physiology/Experimental Medicine |

From the Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Japan.
Correspondence to Norikazu Maeda, MD, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5, Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail nmaeda{at}imed2.med.osaka-u.ac.jp
Abstract
Objectives— Adiponectin is recognized as an antidiabetic, antiatherosclerotic, and anti-inflammatory protein derived from adipocytes. However, the role of adiponectin in cardiac fibrosis remains uncertain. We herein explore the effects of adiponectin on cardiac fibrosis induced by angiotensin II (Ang II).
Methods and Results— Wild-type (WT), adiponectin knockout (Adipo-KO), and PPAR-
knockout (PPAR-
-KO) mice were infused with Ang II at 1.2 mg/kg/d. Severe cardiac fibrosis and left ventricular dysfunction were observed in Ang II–infused Adipo-KO mice compared to WT mice. Adenovirus-mediated adiponectin treatment improved the above phenotypes and the dysregulation of reactive oxygen species (ROS)-related mRNAs in Adipo-KO mice, whereas such amelioration was not observed in PPAR-
-KO mice despite adiponectin accumulation in heart tissue. In cultured cardiac fibroblasts, adiponectin improved the reduction of AMP-activated protein kinase (AMPK) activity and elevation of extracellular signal–regulated kinase 1/2 (ERK1/2) activity induced by Ang II. Adiponectin significantly enhanced PPAR-
activity, whereas the adiponectin-dependent PPAR-
activation was diminished by Compound C, an inhibitor of AMPK.
Conclusion— The present study suggests that adiponectin protects against Ang II–induced cardiac fibrosis possibly through AMPK-dependent PPAR-
activation.
Adiponectin-deficient mice revealed severe angiotensin II–induced cardiac fibrosis and its phenotype were reversed by adiponectin supplementation. However, adiponectin treatment failed to ameliorate cardiac fibrosis in angiotensin II–infused PPAR-
-deficient mice. In vivo and in vitro experiments suggested that adiponectin protects against angiotensin II–induced cardiac fibrosis possibly through AMPK-dependent PPAR-
activation.
Key Words: adiponectin angiotensin II PPAR-
fibrosis AMPK
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