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

Abstract

UNLABELLED:

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.

• Authors: Vaibhav B Patel, Abhijit Takawale, Tharmarajan Ramprasath, Subhash K Das, Ratnadeep Basu, Maria B Grant, David A Hall, Zamaneh Kassiri, Gavin Y Oudit
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 93 Issue 9 Pg. 1003-13 (Sep 2015) ISSN: 1432-1440 [Electronic] Germany
• PMID: 25874965 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 7-Ala-angiotensin (1-7)
• MAS1 protein, human
• Peptide Fragments
• Proto-Oncogene Mas
• Angiotensin II
• Angiotensin I
• Nitric Oxide Synthase Type III
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• angiotensin I (1-7)

Topics

• Angiotensin I (antagonists & inhibitors)
• Angiotensin II (analogs & derivatives, metabolism, pharmacology)
• Angiotensin-Converting Enzyme 2
• Animals
• Cardiovascular Diseases (blood, drug therapy)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Peptide Fragments (antagonists & inhibitors, pharmacology)
• Peptidyl-Dipeptidase A (blood, therapeutic use)
• Proto-Oncogene Mas
• Signal Transduction (drug effects)