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

Heart failure (HF) carries the highest mortality in the western world and β-blockers [β-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac β₁AR-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 and activity, thereby directly increasing cardiac contractility. Given that certain β-blockers, such as carvedilol and metoprolol, can activate βarrestins and/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac βarrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces βarrestin2 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 β₂AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied β₂AR subtype on carvedilol-occupied β₁AR-stimulated, βarrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress βarrestin2, 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 βarrestin2, 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 βarrestin2-mediated SERCA2a SUMOylation and activity through the β₁AR in cardiac myocytes, translating into direct positive inotropy. However, this unique βarrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound β₂AR subtype signaling.