An adrenal beta-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 (betaarr1), 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 betaarr1-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 betaarr, but not G protein coupling to the AT(1)R, recapitulates the effects of AngII on aldosterone production and secretion. In vivo, increased adrenal betaarr1 activity, by means of adrenal-targeted adenoviral-mediated gene delivery of a betaarr1 transgene, resulted in a marked elevation of circulating aldosterone levels in otherwise normal animals, suggesting that this adrenocortical betaarr1-mediated signaling pathway is operative, and promotes aldosterone production and secretion in vivo, as well. Thus, inhibition of adrenal betaarr1 activity on AT(1)Rs might be of therapeutic value in pathological conditions characterized and aggravated by hyperaldosteronism.
Lymperopoulos
Anastasios
A
Center for Translational Medicine and George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Rengo
Giuseppe
G
Zincarelli
Carmela
C
Kim
Jihee
J
Soltys
Stephen
S
Koch
Walter J
WJ
D000311:Adrenal Glands / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D015384:Zona Glomerulosa / Q000166:cytology; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D000098682:Steroidogenic Acute Regulatory Protein
C000605256:Arrb1 protein, rat; D019390:Arrestins; D010750:Phosphoproteins; D044140:Receptor, Angiotensin, Type 1; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D000098682:Steroidogenic Acute Regulatory Protein; D000804:Angiotensin II; D000450:Aldosterone; D048049:Extracellular Signal-Regulated MAP Kinases