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

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

Author information

1
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.
2
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
3
Department of Physiology, University of Alberta, Edmonton, Canada.
4
Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
5
GlaxoSmithKline, Stevenage, UK.
6
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada. gavin.oudit@ualberta.ca.
7
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. gavin.oudit@ualberta.ca.
8
Department of Physiology, University of Alberta, Edmonton, Canada. gavin.oudit@ualberta.ca.

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

PMID:
25874965
PMCID:
PMC4580513
DOI:
10.1007/s00109-015-1285-z
[Indexed for MEDLINE]
Free PMC Article
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