title: The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway.
abstract: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear.
  
  
  OBJECTIVE
  To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway.
  
  
  RESULTS
  In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS.
  
  
  METHODS
  This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS.
  
  
  CONCLUSIONS
  The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.
authors.affiliation: 1 Department of Respiratory Diseases, Nanfang Hospital, the Southern Medical University , Guangzhou, China .
authors.forename: Ying
authors.initials: Y
authors.lastname: Meng
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Gao-Su
authors.initials: GS
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Yu
authors.forename: Miao-Xia
authors.initials: MX
authors.lastname: Pang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Wen-Yong
authors.initials: WY
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000803:Angiotensin I / Q000502:physiology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D005347:Fibroblasts / Q000502:physiology*; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000473:pathology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D000803:Angiotensin I; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D054460:rho-Associated Kinases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D020742:rhoA GTP-Binding Protein; C118790:angiotensin I (1-7)
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