Ang-(1-7) is an endogenous β-arrestin-biased agonist of the AT1 receptor with protective action in cardiac hypertrophy

Sci Rep. 2017 Sep 19;7(1):11903. doi: 10.1038/s41598-017-12074-3.

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 AT1 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 β-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 β-arrestin-biased agonist of the AT1R. Here we show that Ang-(1-7) binds to the AT1R without activating Gq, but triggering β-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 AT1 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 β-arrestin-biased agonist at the AT1R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / metabolism
  • Angiotensin I / therapeutic use*
  • Animals
  • Cardiomegaly / drug therapy*
  • Cardiomegaly / metabolism
  • Cardiomegaly / physiopathology
  • Cardiotonic Agents / metabolism
  • Cardiotonic Agents / therapeutic use*
  • Diastole / drug effects
  • HEK293 Cells
  • Heart / drug effects
  • Heart / physiopathology
  • Humans
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Peptide Fragments / metabolism
  • Peptide Fragments / therapeutic use*
  • Phosphorylation
  • Rats
  • Rats, Inbred WF
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Signal Transduction / drug effects
  • beta-Arrestins / agonists*
  • beta-Arrestins / metabolism

Substances

  • Cardiotonic Agents
  • Peptide Fragments
  • Receptor, Angiotensin, Type 1
  • beta-Arrestins
  • Angiotensin I
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • angiotensin I (1-7)

Grants and funding