Antagonism of angiotensin 1-7 prevents the therapeutic effects of recombinant human ACE2

J Mol Med (Berl). 2015 Sep;93(9):1003-13. doi: 10.1007/s00109-015-1285-z. Epub 2015 Apr 15.

Abstract

Activation of the angiotensin 1-7/Mas receptor (MasR) axis counteracts angiotensin II (Ang II)-mediated cardiovascular disease. Recombinant human angiotensin-converting enzyme 2 (rhACE2) generates Ang 1-7 from Ang II. We hypothesized that the therapeutic effects of rhACE2 are dependent on Ang 1-7 action. Wild type male C57BL/6 mice (10-12 weeks old) were infused with Ang II (1.5 mg/kg/d) and treated with rhACE2 (2 mg/kg/d). The Ang 1-7 antagonist, A779 (200 ng/kg/min), was administered to a parallel group of mice. rhACE2 prevented Ang II-induced hypertrophy and diastolic dysfunction while A779 prevented these beneficial effects and precipitated systolic dysfunction. rhACE2 effectively antagonized Ang II-mediated myocardial fibrosis which was dependent on the action of Ang 1-7. Myocardial oxidative stress and matrix metalloproteinase 2 activity was further increased by Ang 1-7 inhibition even in the presence of rhACE2. Activation of Akt and endothelial nitric oxide synthase (eNOS) by rhACE2 were suppressed by the antagonism of Ang 1-7 while the activation of pathological signaling pathways was maintained. Blocking Ang 1-7 action prevents the therapeutic effects of rhACE2 in the setting of elevated Ang II culminating in systolic dysfunction. These results highlight a key cardioprotective role of Ang 1-7, and increased Ang 1-7 action represents a potential therapeutic strategy for cardiovascular diseases.

Key messages: Activation of the renin-angiotensin system (RAS) plays a key pathogenic role in cardiovascular disease. ACE2, a monocarboxypeptidase, negatively regulates pathological effects of Ang II. Antagonizing Ang 1-7 prevents the therapeutic effects of recombinant human ACE2. Our results highlight a key protective role of Ang 1-7 in cardiovascular disease.

Keywords: Angiotensin 1–7; Angiotensin-converting enzyme 2; PI3K/Akt signaling; Renin–angiotensin system.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / antagonists & inhibitors*
  • Angiotensin II / analogs & derivatives*
  • Angiotensin II / metabolism
  • Angiotensin II / pharmacology
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / drug therapy
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / pharmacology*
  • Peptidyl-Dipeptidase A / blood
  • Peptidyl-Dipeptidase A / therapeutic use*
  • Signal Transduction / drug effects

Substances

  • 7-Ala-angiotensin (1-7)
  • Peptide Fragments
  • Angiotensin II
  • Angiotensin I
  • Nitric Oxide Synthase Type III
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • angiotensin I (1-7)