Carvedilol uniquely stimulates βarrestin2‐dependent SERCA2a Activity via the β1‐ adrenergic receptor to exert positive inotropy in cardiac myocytes
Authors: Parker Barbara Marie , McCrink Katie Anne , Brill Ava , Maning Jennifer , Desimine Victoria L. , Duarte Yanelys , Wertz Shelby Lynn , Lymperopoulos Anastasios 
Published: June 2021

Background

Heart failure (HF) is the number one killer in the western world and β‐blockers are part of its cornerstone pharmacotherapy. We have recently shown that β1‐adrenergic receptor (AR)‐activated βarrestin2, a G protein‐coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA)2a SUMO (small ubiquitin‐like modifier)‐ylation & activity, thereby increasing cardiac contractility. Given that certain βAR antagonists, such as carvedilol and metoprolol, have been shown to activate βarrestins and SERCA2a in the heart, we sought to investigate, in the present study, the effects of these drugs (if any) on cardiac βarrestin2‐dependent SERCA2a SUMOylation & activity.

Methods

We studied SERCA2a‐βarrestin interaction and SERCA2a 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) transfected with βarrestin2 and treated with either drug.

Results

Carvedilol, but not metoprolol, acutely induces βarrestin2 (but not βarrestin1) interaction with SERCA2a in H9c2 cardiomyocytes, resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the β2AR‐selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of this βAR subtype on carvedilol‐bound β1AR‐stimulated, βarrestin2‐dependent SERCA2a activation. In addition, the amplitude of spontaneous cell shortening of NRVMs transiently transfected with βarrestin2 is acutely enhanced by carvedilol, again in the presence of ICI only (122±9% of control, ICI only‐treated NRVMs; p<0.05, n=10). In contrast, metoprolol with (or without) ICI had again no effect on NRVMs` shortening amplitude (98±6% of control, ICI only‐treated NRVMs; p<0.05, n=10).

Conclusions

Carvedilol, but not metoprolol, stimulates βarrestin2‐mediated SERCA2a SUMOylation and activity through the β1AR in cardiac myocytes. This translates into direct positive inotropic effects of this β‐blocker drug in the heart, which, however, might be masked by opposing actions of the cardiac β2AR. These findings challenge the conventional wisdom that all β‐blockers exert negative inotropy in the heart, which usually complicates their use and limits their dosages during chronic HF treatment in humans. Furthermore, our study highlights the particular usefulness of carvedilol for human HF therapy, both acute and chronic, as this agent appears to possess unique, among the β‐blocker class of drugs, positive inotropic properties, on top of its classic (shared by most other agents in the class) reverse remodeling effects.

Support or Funding Information

1) American Heart Association Scientist Development Grant (SDG) 2) NSU President`s Faculty Research & Development Grant (PFRDG)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.