Negative impact of ?-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms.

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

SUBMITTER: Bathgate-Siryk A 

PROVIDER: S-EPMC3889868 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature