Targeting Adiponectin Receptor 1 Phosphorylation Against Ischemic Heart Failure

作者：Di Zhu, Zhen Zhang, Jianli Zhao, Demin Liu, Lu Gan, Wayne Bond Lau, Dina Xie, Zhijun Meng, Peng Yao, Jumpei Tsukuda, Theodore A. Christopher, Bernard L. Lopez, Erhe Gao, Walter J. Koch, Yajing Wang, Xinliang Ma · 发表于：Circulation Research · 年份：2022 · DOI：10.1161/circresaha.121.319976 · 被引用次数：27 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Cardiac Fibrosis and Remodeling、Cardiovascular Function and Risk Factors

Background: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein–coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. Methods: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. Results: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser 205 (AdipoR1 S205A ), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing ...