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

Vaibhav B. Patel, Abhijit Takawale, Tharmarajan Ramprasath, Subhash K. Das, Ratnadeep Basu, Maria B. Grant, David A. Hall, Zamaneh Kassiri, Gavin Y. Oudit

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1003-1013
Number of pages11
JournalJournal of Molecular Medicine
Volume93
Issue number9
DOIs
StatePublished - Sep 26 2015

Keywords

  • Angiotensin 1–7
  • Angiotensin-converting enzyme 2
  • PI3K/Akt signaling
  • Renin–angiotensin system

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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    Patel, V. B., Takawale, A., Ramprasath, T., Das, S. K., Basu, R., Grant, M. B., Hall, D. A., Kassiri, Z., & Oudit, G. Y. (2015). Antagonism of angiotensin 1–7 prevents the therapeutic effects of recombinant human ACE2. Journal of Molecular Medicine, 93(9), 1003-1013. https://doi.org/10.1007/s00109-015-1285-z