title: Endothelin-1 downregulates angiotensin-converting enzyme-2 expression in human bronchial epithelial cells.
abstract: OBJECTIVE
  Both endothelin-1 (ET-1) and the renin-angiotensin system (RAS) are implicated in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). In the present study, we explored the interaction between ET-1 and the RAS by examining the effect of ET-1 on angiotensin-converting enzyme-2 (ACE2) expression and activity in human bronchial epithelial cells (HBEpCs).
  
  
  METHODS
  HBEpCs were treated with ET-1 (1, 10, 20, 40 or 50 nmol/l) for 6, 12, 18, 24 or 30 h with or without the transcription inhibitor actinomycin D, endothelin A (ETA) receptor blocker BQ123, endothelin B receptor blocker BQ788, or different kinase inhibitors.
  
  
  RESULTS
  ET-1 decreased the ACE2 mRNA level in a dose- and time-dependent manner within 24 h, which led to dose-dependent downregulation of the ACE2 promoter activity, protein level and the cell membrane ACE2 activity. Actinomycin D (1 mg/ml), BQ123 (1 μmol/l), and the p38 mitogen-activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 μmol/l) completely abolished the effect of ET-1 on ACE2 expression in HBEpCs.
  
  
  CONCLUSIONS
  ET-1 downregulates ACE2 expression and activity at the transcription level in HBEpCs via the ETA receptor by a p38 MAPK-dependent mechanism. This is the first evidence of crosstalk between the ET-1/ETA axis and the RAS in regard to the pathogenesis and progression of COPD.
authors.affiliation: Department of Emergency, Second Xiangya Hospital, Central South University, Changsha, PR China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhang
authors.forename: Yamin
authors.initials: Y
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.forename: Renrong
authors.initials: R
authors.lastname: Wu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Ou
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D003609:Dactinomycin; D048051:p38 Mitogen-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2