title: The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension.
abstract: BACKGROUND
  An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/AngII type 1 receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin angiotensin system composed of ACE2/Ang-(1-7)/Mas has led us to examine the role of this vasoprotective axis on such disorders.
  
  
  OBJECTIVE
  We hypothesized that Ang-(1-7) treatment would exert protective effects against PF and PH.
  
  
  METHODS
  Lentiviral packaged Ang-(1-7) fusion gene or ACE2 cDNA was intratracheally administered into the lungs of male Sprague Dawley rats. Two weeks after gene transfer, animals received bleomycin (2.5 mg/kg). In a subsequent study, animals were administered monocrotaline (MCT, 50 mg/kg).
  
  
  RESULTS
  In the PF study, bleomycin administration resulted in a significant increase in right ventricular systolic pressure, which was associated with the development of right ventricular hypertrophy. The lungs of these animals also exhibited excessive collagen deposition, decreased expression of ACE and ACE2, increased mRNA levels for transforming growth factor β and other proinflammatory cytokines, and increased protein levels of the AT₁R. Overexpression of Ang-(1-7) significantly prevented all the above-mentioned pathophysiological conditions. Similar protective effects were also obtained with ACE2 overexpression. In the PH study, rats injected with MCT developed elevated right ventricular systolic pressure, right ventricular hypertrophy, right ventricular fibrosis, and pulmonary vascular remodeling, all of which were attenuated by Ang-(1-7) overexpression. Blockade of the Mas receptor abolished the beneficial effects of Ang-(1-7) against MCT-induced PH.
  
  
  CONCLUSIONS
  Our observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(1-7)/Mas axis in the treatment of lung disorders.
authors.affiliation: Department of Pharmacodynamics, University of Florida, Gainesville, Florida, USA.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Shenoy
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ferreira
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Fraga-Silva
authors.forename: Carlos
authors.initials: C
authors.lastname: Díez-Freire
authors.forename: Autumn
authors.initials: A
authors.lastname: Dooies
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Jun
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sriramula
authors.forename: Nithya
authors.initials: N
authors.lastname: Mariappan
authors.forename: Dorna
authors.initials: D
authors.lastname: Pourang
authors.forename: Changaram S
authors.initials: CS
authors.lastname: Venugopal
authors.forename: Joseph
authors.initials: J
authors.lastname: Francis
authors.forename: Timothy
authors.initials: T
authors.lastname: Reudelhuber
authors.forename: Robson A
authors.initials: RA
authors.lastname: Santos
authors.forename: Jawaharlal M
authors.initials: JM
authors.lastname: Patel
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
mesh_terms: D000803:Angiotensin I / Q000235:genetics* / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001761:Bleomycin; D015316:Genetic Therapy; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012084:Renin-Angiotensin System; D014161:Transduction, Genetic
chemical_list: D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D001761:Bleomycin; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)