Abstract 5935: Genetic Deletion of β-arrestin-1 Improves Function of the Infarcted Heart by Reducing Cardiac β-adrenergic Receptor Desensitization and Cardiotoxic Neurohormonal Overstimulation
Chronic heart failure (HF) is characterized by enhanced circulating catecholamines (CA’s) and aldosterone, which contribute to its morbidity and mortality. Catecholaminergic overstimulation of the failing heart compromises function and increases its workload, while aldosterone accelerates cardiac adverse remodeling post-myocardial infarction (MI). Cardiac β-adrenergic receptor (AR) desensitization/downregulation is a hallmark molecular abnormality in HF and is due to the concerted action of cardiac G-protein coupled receptor kinase-2 (GRK2), which is up-regulated in HF, together with its co-factors in receptor desensitization, the β-arrestins (βarrs). Consistent with this, βarr1 knockout (KO) mice exhibit enhanced cardiac contractile responsiveness to catecholamines. Additionally, we recently reported that βarr1 promotes angiotensin II-dependent aldosterone production in the adrenal cortex, leading to elevated circulating aldosterone levels in vivo. Herein, we sought to investigate the effects of genetically deleting βarr1 on post-MI cardiac function and neurohormonal status in mice. We used the βarr1KO mouse model, which we studied at 4 weeks after surgically-induced MI, alongside wild type (WT) controls. Cardiac function was assessed by echocardiography and in vivo catheterization. Plasma CAs and aldosterone were measured by ELISA and cardiac βAR signaling status was examined, as well. Cardiac function is markedly improved in βarr1KO’s at 4 weeks post-MI, as evidenced by increased ejection fraction compared to WT mice (41.5 ± 2.8 % vs. 21.8 ± 2.4 %, respectively, n=9, p<0.0001) and increased isoproterenol-induced contractility. Additionally, cardiac dimensions are significantly reduced compared to WT’s, indicating attenuated adverse remodeling. Moreover, plasma norepinephrine, epinephrine and aldosterone levels are significantly reduced and cardiac cAMP and βAR plasma membrane density are robustly elevated in post-MI βarr1KO’s compared to WT’s. Thus, genetic deletion of βarr1 prevents post-MI HF-associated cardiac βAR desensitization/downregulation and improves the neurohormonal burden of the post-MI heart. As a result, cardiac function is significantly improved and adverse remodeling is attenuated.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).