title: Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway.
abstract: Accumulating evidence has demonstrated that up-regulation of the angiotensin (Ang)-converting enzyme (ACE)/AngII/AngII type 1 receptor (AT1R) axis aggravates pulmonary fibrosis. The recently discovered ACE2/Ang-(1-7)/Mas axis, which counteracts the activity of the ACE/AngII/AT1R axis, has been shown to protect against pulmonary fibrosis. However, the mechanisms by which ACE2 and Ang-(1-7) attenuate pulmonary fibrosis remain unclear. We hypothesized that up-regulation of the ACE2/Ang-(1-7)/Mas axis protects against bleomycin (BLM)-induced pulmonary fibrosis by inhibiting the mitogen-activated protein kinase (MAPK)/NF-κB pathway. In vivo, Ang-(1-7) was continuously infused into Wistar rats that had received BLM or AngII. In vitro, human fetal lung-1 cells were pretreated with compounds that block the activities of AT1R, Mas (A-779), and MAPKs before exposure to AngII or Ang-(1-7). The human fetal lung-1 cells were infected with lentivirus-mediated ACE2 before exposure to AngII. In vivo, Ang-(1-7) prevented BLM-induced lung fibrosis and AngII-induced lung inflammation by inhibiting the MAPK phosphorylation and NF-κB signaling cascades. However, exogenous Ang-(1-7) alone clearly promoted lung inflammation. In vitro, Ang-(1-7) and lentivirus-mediated ACE2 inhibited the AngII-induced MAPK/NF-κB pathway, thereby attenuating inflammation and α-collagen I production, which could be reversed by the Mas inhibitor, A-779. Ang-(1-7) inhibited AngII-induced lung fibroblast apoptotic resistance via inhibition of the MAPK/NF-κB pathway and activation of the BCL-2-associated X protein/caspase-dependent mitochondrial apoptotic pathway. Ang-(1-7) alone markedly stimulated extracellular signal-regulated protein kinase 1/2 phosphorylation and the NF-κB cascade. Up-regulation of the ACE2/Ang-(1-7)/Mas axis protected against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway. However, close attention should be paid to the proinflammatory effects of Ang-(1-7).
authors.affiliation: 1 Department of Respiratory Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Meng
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Shan
authors.initials: S
authors.lastname: Huang
authors.forename: Ping-Sheng
authors.initials: PS
authors.lastname: Wu
authors.forename: Shao-Xi
authors.initials: SX
authors.lastname: Cai
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D055104:Infusions, Subcutaneous; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010766:Phosphorylation; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C494813:Bcl2l1 protein, rat; D024042:Collagen Type I; D016328:NF-kappa B; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D051020:bcl-X Protein; D001761:Bleomycin; D000804:Angiotensin II; D000803:Angiotensin I; D048049:Extracellular Signal-Regulated MAP Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)