title: Antagonism of angiotensin 1-7 prevents the therapeutic effects of recombinant human ACE2.
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.
  
  
  CONCLUSIONS
  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: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors: Vaibhav B
authors: VB
authors: Patel
authors: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.|Department of Physiology, University of Alberta, Edmonton, Canada.
authors: Abhijit
authors: A
authors: Takawale
authors: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors: Tharmarajan
authors: T
authors: Ramprasath
authors: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors: Subhash K
authors: SK
authors: Das
authors: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, 8440 112 Street NW, Edmonton, AB, T6G 2B7, Canada.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.
authors: Ratnadeep
authors: R
authors: Basu
authors: Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Maria B
authors: MB
authors: Grant
authors: GlaxoSmithKline, Stevenage, UK.
authors: David A
authors: DA
authors: Hall
authors: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada.|Department of Physiology, University of Alberta, Edmonton, Canada.
authors: Zamaneh
authors: Z
authors: Kassiri
authors: 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.|Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. gavin.oudit@ualberta.ca.|Department of Physiology, University of Alberta, Edmonton, Canada. gavin.oudit@ualberta.ca.
authors: Gavin Y
authors: GY
authors: Oudit
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C092006:7-Ala-angiotensin (1-7); C000715470:MAS1 protein, human; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D000804:Angiotensin II; D000803:Angiotensin I; D052250:Nitric Oxide Synthase Type III; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)
keywords: Angiotensin 1–7; Angiotensin-converting enzyme 2; PI3K/Akt signaling; Renin–angiotensin system