An adrenal β-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo

Aldosterone produces a multitude of effects in vivo, including promotion of postmyocardial infarction adverse cardiac remodeling and heart failure progression. It is produced and secreted by the adrenocortical zona glomerulosa (AZG) cells after angiotensin II (AngII) activation of AngII type 1 receptors (AT(1)Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of G(q/11)-proteins, to which the AT(1)R normally couples. Here, we describe a novel signaling pathway underlying this AT(1)R-dependent aldosterone production mediated by beta-arrestin-1 (beta arr1), a universal heptahelical receptor adapter/scaffolding protein. This pathway results in sustained ERK activation and subsequent up-regulation of steroidogenic acute regulatory protein, a steroid transport protein regulating aldosterone biosynthesis in AZG cells. Also, this beta arr1-mediated pathway appears capable of promoting aldosterone turnover independently of G protein activation, because treatment of AZG cells with SII, an AngII analog that induces beta arr, but not G protein coupling to the AT(1)R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal beta arr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a beta arr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical beta arr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal beta arr1 activity on AT(1)Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism.