β-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes

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 beta arr (beta-arrestin)-1 and beta arr-2 are functionally distinct in the heart. beta arr1 is cardiotoxic, decreasing contractility by opposing beta(1)AR (adrenergic receptor) signaling and promoting apoptosis/ inflammation post-myocardial infarction (MI). Conversely, beta arr2 inhibits apoptosis/ inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether beta arr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that beta arr2 directly interacts with SERCA2a (sarco[ endo] plasmic reticulum Ca2+-ATPase) in vivo and in vitro in a beta(1)AR-dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin-like modifier)ylation, increasing SERCA2a activity and thus, cardiac contractility. beta arr1 lacks this effect. Moreover, beta arr2 does not desensitize beta(1)AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to beta arr1. In vivo, post-MI heart failure mice overexpressing cardiac beta arr2 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, beta arr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac beta AR number or cAMP levels in vivo. In conclusion, enhancement of cardiac beta arr2 levels/ signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post-MI remodeling. Thus, cardiac beta arr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure.