Abstract 9543: βArrestin1 Genetic Deletion Improves Cardiac Function and Adverse Remodeling in Heart Failure

Abstract

Introduction: Chronic heart failure (HF) is characterized by enhanced circulating cardiotoxic hormones, including catecholamines and aldosterone, which contribute to the increased morbidity and mortality associated with myocardial infarction (MI). Cardiac ß-adrenergic receptor (AR) desensitization is a hallmark molecular abnormality in HFand is due to the concerted action of cardiac G protein-coupled receptor kinase-2 (GRK2), together with its co-factors in receptor desensitization, the ßarrestins (ßarrs). We have also recently established that ßarr1 promotes angiotensin II-dependent aldosterone production in the adrenal cortex, and this leads to elevated circulating aldosterone levels in vivo, both under normal conditions and during post-MI HF progression. Hypothesis: Herein, we sought to investigate the effects of genetic deletion of ßarr1 on post-MI cardiac function and structure in mice progressing to HF. Methods: We utilized the global ßarr1 knockout (KO) mouse model and studied these mice at 4 weeks after surgically induced MI, in parallel with C57/Bl6 wild type (WT) controls. Cardiac function was assessed by echocardiography and in vivo catheterization. Plasma hormones were measured by ELISA. Adverse remodeling markers` mRNA expression was assessed by real time PCR. Results: Cardiac function is markedly improved in ßarr1KO`s at 4 weeks post-MI compared to WT mice (ejection fraction: 41.5±2.8% vs. 21.8±2.4%, respectively, n=9, p<0.0001). Isoproterenol-induced contractility is also enhanced. Additionally, cardiac dimensions are significantly reduced compared to WT`s, as are levels of adverse remodeling markers, indicating attenuation of adverse cardiac remodeling. Importantly, plasma circulating aldosterone and catecholamine levels are significantly lowered and cardiac ßAR signaling and function appear elevated in post-MI ßarr1KO`s compared to control WT`s. Conclusions: Genetic deletion of ßarr1 substantially improves cardiac function, adverse remodeling, neurohormonal status and ßAR function during post-MI HF progression. The underlying mechanism appears to be attenuation of both cardiac ßAR desensitization and adrenal cardiotoxic hormone production, both ßarr1-dependent phenomena.