Abstract 099: Carvedilol Selectively Stimulates Beta-arrestin2-dependent Serca2a Activity in Cardiomyocytes to Augment Contractility

Abstract

Background: Heart failure (HF) is the number one killer in the western world and β-blockers are part of its cornerstone pharmacotherapy. We recently showed that β 1 -adrenergic receptor (AR)-activated βarrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation & activity, thereby increasing cardiac contractility. Given that carvedilol, unlike other β-blockers, has been shown to activate βarrestins and SERCA2a in the heart, we investigated herein its effects on βarrestin2-dependent SERCA2a modulation and contractility. Methods: We studied SERCA2a-βarrestin interactions, SUMOylation & activity in response to therapeutic doses of carvedilol or metoprolol in H9c2 cardiac cells. We also measured contraction amplitude (cell shortening) of neonatal rat ventricular myocytes (NRVMs). Results: Carvedilol, unlike metoprolol, acutely induces βarrestin2 (not βarrestin1) interaction with SERCA2a in H9c2 cardiomyocytes, resulting in enhanced SERCA2a SUMOylation. This translates into enhanced SERCA2a activity in the presence of the β 2 AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of β 2 AR on carvedilol-stimulated, βarrestin2-dependent SERCA2a activation in H9C2 cells. In addition, the amplitude of spontaneous cell shortening of βarrestin2-overexpressing NRVMs is enhanced by carvedilol, especially in the presence of ICI (122+9% of control, ICI only-treated NRVMs; p<0.05, n=10). In contrast, metoprolol alone or with ICI had no effect again (98+6% of control, ICI only-treated NRVMs; p<0.05, n=10). Conclusions: Carvedilol uniquely stimulates βarrestin2-mediated SERCA2a SUMOylation/activity through the β 1 AR in cardiac myocytes. This translates into direct positive inotropic effects of this β-blocker, which may be opposed by the cardiac β 2 AR subtype. These findings challenge the conventional wisdom that all β-blockers exert negative inotropy in the heart, complicating their use in human chronic HF treatment, and highlight the particular usefulness of carvedilol for treating this disease, as this drug may have positive inotropic properties on top of its classic reverse remodeling effects.