| Autor: |
Valero TR; Department of Pharmaceutical Sciences Laboratory for the Study of Neurohormonal Control of the Circulation Nova Southeastern University College of Pharmacy Fort Lauderdale Florida 33328., Sturchler E; Translational Research Institute Scripps Florida Jupiter Florida 33458., Jafferjee M; Department of Pharmaceutical Sciences Laboratory for the Study of Neurohormonal Control of the Circulation Nova Southeastern University College of Pharmacy Fort Lauderdale Florida 33328., Rengo G; Salvatore Maugeri Foundation-Scientific Institute of Telese Terme Telese Terme Italy., Magafa V; Department of Pharmacy Laboratory of Pharmacognosy & Chemistry of Natural Products University of Patras Patras Greece., Cordopatis P; Department of Pharmacy Laboratory of Pharmacognosy & Chemistry of Natural Products University of Patras Patras Greece., McDonald P; Translational Research Institute Scripps Florida Jupiter Florida 33458., Koch WJ; Center for Translational Medicine Temple University Philadelphia Pennsylvania 19140., Lymperopoulos A; Department of Pharmaceutical Sciences Laboratory for the Study of Neurohormonal Control of the Circulation Nova Southeastern University College of Pharmacy Fort Lauderdale Florida 33328. |
| Abstrakt: |
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 β-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 β-arrestin-dependent signaling at the AT1R have been designed and described, starting with SII, the gold-standard β-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 β-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 β-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 β-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 β-arrestin activation. These findings provide important insights for AT1R pharmacology and future AngII-targeted drug development. |
