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

Abstract

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 (AT1Rs). Until now, the general consensus for AngII signaling to aldosterone production has been that it proceeds via activation of Gq/11-proteins, to which the AT1R normally couples. Here, we describe a novel signaling pathway underlying this AT1R-dependent aldosterone production mediated by ␤-arrestin-1 (␤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 ␤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 ␤arr, but not G protein coupling to the AT1R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal ␤arr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a ␤arr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical ␤arr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal ␤arr1 activity on AT1Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism.adrenocortical zona glomerulosa cell ͉ G protein-coupled receptor ͉ angiotensin II receptor type I ͉ adrenal steroid hormones ͉ biased agonism

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“…Of note, Lymperopoulos et al recently reported that aldosterone secretion through AT1R was mediated by ß-arrestin. 29 This was shown in vitro in the human adrenocortical zona glomerulosa cell line H295R and in vivo in normal rats with adrenal gland-specific overexpression of ß-arrestin1. Transfection of the H295R cells with a dominant negative ß-arrestin1 mutant significantly reduced angiotensin-induced aldosterone production.…”

Which ARB drug is better for heart failure therapy? Aldosterone suppression holds the answer

“…Next, we examined the impact of this on the physiological effect of AT1R-induced aldosterone production in vitro. Using the human AZG cell line H295R, transfected to overexpress arr1 [4] , and in vitro aldosterone secretion as the readout, we found that candesartan and valsartan are by far the most potent aldosterone secretion inhibitors in vitro ( Fig. 1) [11] .…”

“…1), which significantly exacerbates post-MI HF [4][5][6] . Of note, the prototypic drug of the ARB class losartan appears ineffective at blocking the adrenal arr1-dependent aldosterone production and hence, at suppressing circulating aldosterone post-MI [5] .…”

ARBs and adrenal aldosterone: the beta-arrestin1 connection

“…Next, we examined the impact of this on the physiological effect of AT1R-induced aldosterone production in vitro. Using the human AZG cell line H295R, transfected to overexpress arr1 [4] , and in vitro aldosterone secretion as the readout, we found that candesartan and valsartan are by far the most potent aldosterone secretion inhibitors in vitro [11] . Olmesartan also displays some limited capability of suppressing secretion but losartan and irbesartan are…”

“…AT1R is a G protein-coupled receptor (GPCR) that also signals through G protein-independent pathways, a plethora of which are mediated by the scaffolding actions of arrestins (arrs), originally discovered as terminators of GPCR signaling [3] . AngII elicits aldosterone synthesis and secretion via both G proteins and arrs (specifically arr1) [4][5][6] . Of note, the prototypic drug of the ARB class losartan appears ineffective at blocking the adrenal arr1-dependent aldosterone production and hence, at suppressing circulating aldosterone [5] .…”