Abstract 9478: GRK2-Mediated Phosphorylative Desensitization of AdipoR1 in the Failing Heart
Adiponectin (APN) is a novel adipokine whose cardioprotective actions in acute myocardial infarction (MI) are well-defined. However, the role of APN in chronic heart failure (HF) is controversial. Experimental studies demonstrate APN deficiency exacerbates HF progression. Paradoxically, clinical observations report APN increases in relation to worsening HF. Here, we determine whether APN receptors 1 and 2 (AdipoR1/AdipoR2, the 7-transmembrane domain-containing receptors mediating APN actions) are phosphorylatively modified post-MI, similar to G-protein coupled receptors (GPCR), impeding APN signaling. Receptor phosphorylation, kinase expression, and APN function were determined via in vivo, ex vivo, and in vitro models. Neither AdipoR1 nor AdipoR2 were phosphorylated in the normal heart. However, AdipoR1 was phosphorylated post-MI, peaking at 7 days, and remained significantly phosphorylated thereafter. The extent of post-MI AdipoR1 phosphorylation positively correlated with the expression level of GPCR kinease-2 (GRK2). Cardiac-specific GRK2 knockdown virtually abolished post-MI AdipoR1 phosphorylation, whereas virus-mediated GRK2 overexpression significantly phosphorylated AdipoR1 and blocked APN metabolic-regulatory/anti-inflammatory signaling. Ex vivo experiments demonstrated AMPK activation and anti-TNFα effect of APN were significantly inhibited in cardiomyocytes isolated from non-ischemic cardiac regions 7 days post-MI. In vivo experiments demonstrated that acute APN administration induced cardiac GLUT4 translocation, and eNOS phosphorylation was blunted 7 days post-MI. Continuous APN administration beginning 7 days post-MI failed to protect against adverse cardiac remodeling and HF progression in WT mice, which was restored by cardiac-specific GRK2 knockdown. These results demonstrate for the first time that the cardiometabolic-regulatory, anti-inflammatory, and cardioprotective functions of APN are significantly impaired by GRK2-mediated AdipoR1 phosphorylative desensitization during post-MI HF development, suggesting that inhibiting GRK2-mediated AdipoR1 phosphorylation may be a novel therapeutic target, restoring APN signaling and mitigating post-MI remodeling and HF.
Author Disclosures: Y. Wang: None. E. Gao: None. W. Lau: None. Y. Yuan: None. T. Christopher: None. B. Lopez: None. W. Koch: None. X. Ma: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.