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

dc.contributor.authorPatel, Vaibhav B.
dc.contributor.authorTakawale, Abhijit
dc.contributor.authorRamprasath, Tharmarajan
dc.contributor.authorDas, Subhash K.
dc.contributor.authorBasu, Ratnadeep
dc.contributor.authorGrant, Maria B.
dc.contributor.authorHall, David A.
dc.contributor.authorKassiri, Zamaneh
dc.contributor.authorOudit, Gavin Y.
dc.contributor.departmentDepartment of Medicine, IU School of Medicineen_US
dc.description.abstractActivation 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_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationPatel, 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.
dc.relation.journalJournal of Molecular Medicineen_US
dc.rightsPublisher Policyen_US
dc.subjectAngiotensin 1–7en_US
dc.subjectAngiotensin-converting enzyme 2en_US
dc.subjectPI3K/Akt signalingen_US
dc.subjectRenin–angiotensin systemen_US
dc.titleAntagonism of angiotensin 1-7 prevents the therapeutic effects of recombinant human ACE2en_US
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