Negative Impact of β-Arrestin-1 on Post-Myocardial Infarction Heart Failure via Cardiac and Adrenal-Dependent Neurohormonal Mechanisms

beta-Arrestin (beta arr)-1 and beta-arrestin-2 (beta arrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac beta-adrenergic receptor (beta AR) function via beta AR desensitization and downregulation. In addition, they mediate G-protein-independent beta AR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each beta arr isoform in cardiac beta AR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal beta arr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of beta arr1 in post-myocardial infarction (MI) HF by testing the effects of beta arr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied beta arr1 knockout (beta arr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) beta arr1KO mice display enhanced beta AR-dependent contractility and post-MI beta arr1KO mice enhanced overall cardiac function (and beta AR-dependent contractility) compared with wild type. Post-MI beta arr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac beta AR signaling and function, as evidenced by increased beta AR density and procontractile signaling, via reduced cardiac beta AR desensitization because of cardiac beta arr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal beta arr1 absence. Thus, beta arr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.