Carvedilol Selectively Stimulates βArrestin2-Dependent SERCA2a Activity in Cardiomyocytes to Augment Contractility

Heart failure (HF) carries the highest mortality in the western world and beta-blockers [beta-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac beta(1)AR-activated beta arrestin2, a G protein-coupled receptor (GPCR) adapter protein, promotes Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a SUMO (small ubiquitin-like modifier)-ylation and activity, thereby directly increasing cardiac contractility. Given that certain beta-blockers, such as carvedilol and metoprolol, can activate beta arrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac beta arrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces beta arrestin2 interaction with SERCA2a in H9c2 cardiomyocytes and in neonatal rat ventricular myocytes (NRVMs), resulting in enhanced SERCA2a SUMOylation. However, this translates into enhanced SERCA2a activity only in the presence of the beta(2)AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied beta(2)AR subtype on carvedilol-occupied beta(1)AR-stimulated, beta arrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress beta arrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs' shortening amplitude irrespective of ICI co-treatment. Importantly, the pro-contractile effect of carvedilol was also observed in human induced pluripotent stem cell (hIPSC)-derived cardiac myocytes (CMs) overexpressing beta arrestin2, and, in fact, it was present even without concomitant ICI treatment of human CMs. Metoprolol with or without concomitant ICI did not affect contractility of human CMs, either. In conclusion, carvedilol, but not metoprolol, stimulates beta arrestin2-mediated SERCA2a SUMOylation and activity through the beta(1)AR in cardiac myocytes, translating into direct positive inotropy. However, this unique beta arrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound beta(2)AR subtype signaling.

Automated summary

Carvedilol, but not metoprolol, can stimulate beta arrestin2-mediated SERCA2a SUMOylation and activity, leading to enhanced cardiac contractility. However, this effect may be opposed or masked by carvedilol-bound beta(2)AR subtype signaling.