Ang-(1-7) is an endogenous beta-arrestin-biased agonist of the AT(1) receptor with protective action in cardiac hypertrophy

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Teixeira, Larissa B. ; Parreiras-e-Silva, Lucas T. ; Bruder-Nascimento, Thiago ; Duarte, Diego A. ; Simoes, Sarah C. ; Costa, Rafael M. ; Rodriguez, Deisy Y. ; Ferreira, Pedro A. B. ; Silva, Carlos A. A. ; Abrao, Emiliana P. ; Oliveira, Eduardo B. ; Bouvier, Michel ; Tostes, Rita C. ; Costa-Neto, Claudio M.

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, SEP 19 2017.
• Web of Science Citations: 20

Abstract

The renin-angiotensin system (RAS) plays a key role in the control of vasoconstriction as well as sodium and fluid retention mediated mainly by angiotensin (Ang) II acting at the AT(1) receptor (AT1R). Ang(1-7) is another RAS peptide, identified as the endogenous ligand of the Mas receptor and known to counterbalance many of the deleterious effects of AngII. AT1R signaling triggered by beta-arrestin-biased agonists has been associated to cardioprotection. Because position 8 in AngII is important for G protein activation, we hypothesized that Ang-(1-7) could be an endogenous beta-arrestin-biased agonist of the AT1R. Here we show that Ang-(1-7) binds to the AT1R without activating Gq, but triggering beta-arrestins 1 and 2 recruitment and activation. Using an in vivo model of cardiac hypertrophy, we show that Ang-(1-7) significantly attenuates heart hypertrophy by reducing both heart weight and ventricular wall thickness and the increased end-diastolic pressure. Whereas neither the single blockade of AT(1) or Mas receptors with their respective antagonists prevented the cardioprotective action of Ang1-7, combination of the two antagonists partially impaired the effect of Ang-(1-7). Taken together, these data indicate that Ang(1-7) mediates at least part of its cardioprotective effects by acting as an endogenous beta-arrestin-biased agonist at the AT1R. (AU)

• FAPESP's process: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
• Grantee: Claudio Miguel da Costa Neto
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/50086-4 - Development of biosensors for monitoring signaling in subcellular compartments: a powerful molecular tool for drug discovery
• Grantee: Claudio Miguel da Costa Neto
• Support Opportunities: Regular Research Grants