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

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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.

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Authors contribution

VBP, AT, TR, SKD, RB, MBG, DAH, and ZK performed experiments, analyzed, and interpreted the data. GYO designed the research and supervised the project. All authors read and approved the final version of the paper.

Funding

We acknowledge the funding support from CIHR, HSF, AI-HS, and GlaxoSmithKline (GSK) to GYO and HL110170 to MBG and GYO. VBP is supported by AI-HS and HSF postdoctoral fellowships. SKD is supported by an AI-HS graduate studentship.

Disclosures

Our research was supported by a research grant from GlaxoSmithKline.

Author information

Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada

    Vaibhav B. Patel, Tharmarajan Ramprasath, Subhash K. Das, Ratnadeep Basu & Gavin Y Oudit

  2. Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada

    Vaibhav B. Patel, Abhijit Takawale, Tharmarajan Ramprasath, Subhash K. Das, Ratnadeep Basu, Zamaneh Kassiri & Gavin Y Oudit

  3. Department of Physiology, University of Alberta, Edmonton, Canada

    Abhijit Takawale, Zamaneh Kassiri & Gavin Y Oudit

  4. Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA

    Maria B. Grant

  5. GlaxoSmithKline, Stevenage, UK

    David A. Hall

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  1. Vaibhav B. Patel
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  2. Abhijit Takawale
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  9. Gavin Y Oudit
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Correspondence to Gavin Y Oudit.

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Patel, V.B., Takawale, A., Ramprasath, T. et al. Antagonism of angiotensin 1–7 prevents the therapeutic effects of recombinant human ACE2. J Mol Med 93, 1003–1013 (2015). https://doi.org/10.1007/s00109-015-1285-z

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