Adiponectin Protects Against Angiotensin II–Induced Cardiac Fibrosis Through Activation of PPAR-α

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-α knockout (PPAR-α-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-α-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-α activity, whereas the adiponectin-dependent PPAR-α 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-α activation.