{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:06:31Z","timestamp":1789095991713,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"American Heart Association Scientist Development Grant","award":["AHA 09SDG2010138"],"award-info":[{"award-number":["AHA 09SDG2010138"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure (HF) carries the highest mortality in the western world and \u03b2-blockers [\u03b2-adrenergic receptor (AR) antagonists] are part of the cornerstone pharmacotherapy for post-myocardial infarction (MI) chronic HF. Cardiac \u03b21AR-activated \u03b2arrestin2, 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 \u03b2-blockers, such as carvedilol and metoprolol, can activate \u03b2arrestins and\/or SERCA2a in the heart, we investigated the effects of these two agents on cardiac \u03b2arrestin2-dependent SERCA2a SUMOylation and activity. We found that carvedilol, but not metoprolol, acutely induces \u03b2arrestin2 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 \u03b22AR-selective inverse agonist ICI 118,551 (ICI), indicating an opposing effect of carvedilol-occupied \u03b22AR subtype on carvedilol-occupied \u03b21AR-stimulated, \u03b2arrestin2-dependent SERCA2a activation. In addition, the amplitude of fractional shortening of NRVMs, transfected to overexpress \u03b2arrestin2, is acutely enhanced by carvedilol, again in the presence of ICI only. In contrast, metoprolol was without effect on NRVMs\u2019 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 \u03b2arrestin2, 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 \u03b2arrestin2-mediated SERCA2a SUMOylation and activity through the \u03b21AR in cardiac myocytes, translating into direct positive inotropy. However, this unique \u03b2arrestin2-dependent pro-contractile effect of carvedilol may be opposed or masked by carvedilol-bound \u03b22AR subtype signaling.<\/jats:p>","DOI":"10.3390\/ijms231911315","type":"journal-article","created":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T03:34:17Z","timestamp":1664163257000},"page":"11315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Carvedilol Selectively Stimulates \u03b2Arrestin2-Dependent SERCA2a Activity in Cardiomyocytes to Augment Contractility"],"prefix":"10.3390","volume":"23","author":[{"given":"Jennifer","family":"Maning","sequence":"first","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria L.","family":"Desimine","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celina M.","family":"Pollard","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Ghandour","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9817-6319","authenticated-orcid":false,"given":"Anastasios","family":"Lymperopoulos","sequence":"additional","affiliation":[{"name":"Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nrcardio.2012.145","article-title":"Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy","volume":"9","author":"Kho","year":"2012","journal-title":"Nat. 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