Abstract 9951: Cardiac GRK2 Inhibition via ARKct Augments 2-adrenergic Receptor-dependent Contractility and Survival Post-Myocardial Infarction

Abstract

Rationale: β 1 and β 2 -adrenergic receptors (βARs) play distinct roles in the heart, e.g. β 1 AR is pro-contractile and pro-apoptotic but β 2 AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade in vivo might enhance the pro-contractile and anti-apoptotic signaling of the cardiac β 2 AR. Objective: We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β 2 AR signaling post-myocardial infarction (MI). Methods and Results: We crossed β 1 AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a peptide inhibitor of GRK2, and studied the offspring under normal conditions and post-MI. βARKct expression in vivo leads to significantly enhanced β 2 AR-dependent cardiac function, in part via reduction of phosphodiesterase (PDE)4D recruitment to the receptor (ejection fraction in sham-operated, healthy mice: 70+1.1% in βARKct/B1KO`s vs. 59+1.77% in B1KO`s, p<0.05, n=7, and in 4-week post-MI mice: 41.3+3% in βARKct/B1KO`s vs. 25+1.2% in B1KO`s, p<0.05, n=7). In addition, βARKct/B1KO`s have decreased heart dilatation and infarct size, and increased survival at 4 weeks post-MI compared to control B1KO mice. These phenotypic effects are secondary to decreased apoptosis (mediated by Bcl-2 elevation) and increased wound healing-associated inflammation (mediated by NF-κB activation) in βARKct/B1KO hearts very early (at 24 hrs) post-MI vs. B1KO controls. Conclusions: GRK2 inhibition via βARKct markedly augments cardiac β 2 AR beneficial (pro-contractile and anti-apoptotic) signaling post-MI, and thus might be useful for β 2 AR agonist drug therapy in heart failure, e.g. in post-MI patients awaiting cardiac transplantation.