Structure-activity relationship study of angiotensin II analogs in terms of ?-arrestin-dependent signaling to aldosterone production.

ABSTRACT: The known angiotensin II (AngII) physiological effect of aldosterone synthesis and secretion induction, a steroid hormone that contributes to the pathology of postmyocardial infarction (MI) heart failure (HF), is mediated by both Gq/11 proteins and ?-arrestins, both of which couple to the AngII type 1 receptors (AT1Rs) of adrenocortical zona glomerulosa (AZG) cells. Over the past several years, AngII analogs with increased selectivity ("bias") toward ?-arrestin-dependent signaling at the AT1R have been designed and described, starting with SII, the gold-standard ?-arrestin-"biased" AngII analog. In this study, we examined the relative potencies of an extensive series of AngII peptide analogs at relative activation of G proteins versus ?-arrestins by the AT1R. The major structural difference of these peptides from SII was their varied substitutions at position 5, rather than position 4 of native AngII. Three of them were found biased for ?-arrestin activation and extremely potent at stimulating aldosterone secretion in AZG cells in vitro, much more potent than SII in that regard. Finally, the most potent of these three ([Sar(1), Cys(Et)(5), Leu(8)]-AngII, CORET) was further examined in post-MI rats progressing to HF and overexpressing adrenal ?-arrestin1 in vivo. Consistent with the in vitro studies, CORET was found to exacerbate the post-MI hyperaldosteronism, and, consequently, cardiac function of the post-MI animals in vivo. Finally, our data suggest that increasing the size of position 5 of the AngII peptide sequence results in directly proportional increases in AT1R-dependent ?-arrestin activation. These findings provide important insights for AT1R pharmacology and future AngII-targeted drug development.

SUBMITTER: Valero TR 

PROVIDER: S-EPMC4804318 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature