Patel, Vaibhav B.Takawale, AbhijitRamprasath, TharmarajanDas, Subhash K.Basu, RatnadeepGrant, Maria B.Hall, David A.Kassiri, ZamanehOudit, Gavin Y.2015-12-022015-12-022015-09Patel, V. B., Takawale, A., Ramprasath, T., Das, S. K., Basu, R., Grant, M. B., … Oudit, G. Y. (2015). Antagonism of angiotensin 1–7 prevents the therapeutic effects of recombinant human ACE2. Journal of Molecular Medicine (Berlin, Germany), 93(9), 1003–1013. http://doi.org/10.1007/s00109-015-1285-zhttps://hdl.handle.net/1805/7594Activation 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.en-USPublisher PolicyAngiotensin 1–7Angiotensin-converting enzyme 2PI3K/Akt signalingRenin–angiotensin systemArticle