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Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein–coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotoxic, decreasing contractility by opposing β1 AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post–myocardial infarction (MI). Conversely, βarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether βarr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that βarr2 directly interacts with SERCA2a (sarco[endo]plasmic reticulum Ca2+ -ATPase) in vivo and in vitro in a β1 AR-dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin-like modifier)-ylation, increasing SERCA2a activity and thus, cardiac contractility. βarr1 lacks this effect. Moreover, βarr2 does not desensitize β1 AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to βarr1. In vivo, post-MI heart failure mice overexpressing cardiac βarr2 have markedly improved cardiac function, apoptosis, inflammation, and adverse remodeling markers, as well as increased SERCA2a SUMOylation, levels, and activity, compared with control animals. Notably, βarr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac βAR number or cAMP levels in vivo. In conclusion, enhancement of cardiac βarr2 levels/signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post-MI remodeling. Thus, cardiac βarr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure.

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β-Arrestin2 Improves Post–Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca <sup>2+</sup> -ATPase–Dependent Positive Inotropy in Cardiomyocytes

β-Arrestin2 Improves Post–Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca 2+ -ATPase–Dependent Positive Inotropy in Cardiomyocytes

β-Arrestin2 Improves Post–Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca ²⁺ -ATPase–Dependent Positive Inotropy in Cardiomyocytes