title: Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts.
abstract: BACKGROUND
  Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung disease in neonates, but the role of ACE-2 in neonatal lung fibrosis is unknown. We hypothesized that ACE-2 in human fetal lung cells might be downregulated by hyperoxic gas.
  
  
  METHODS
  Fetal human lung fibroblast IMR90 cells were exposed to hyperoxic (95% O2/5% CO2) or normoxic (21% O2/5% CO2) gas in vitro. Cells and culture media were recovered separately for assays of ACE-2 enzymatic activity, mRNA, and immunoreactive protein.
  
  
  RESULTS
  Hyperoxia decreased ACE-2 immunoreactive protein and enzyme activity in IMR90 cells (both P < 0.01), but did not change ACE-2 mRNA. ACE-2 protein was increased in the cell supernatant, suggesting protease-mediated ectodomain shedding. TAPI-2, an inhibitor of TNF-α-converting enzyme (TACE/ADAM17), prevented both the decrease in cellular ACE-2 and the increase in soluble ACE-2 (both P < 0.05).
  
  
  CONCLUSIONS
  These data show that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas. They also suggest that hyperoxia decreases ACE-2 through a shedding mechanism mediated by ADAM17/TACE.
authors: Department of Pediatrics/Neonatology, Michigan State University, East Lansing, Michigan.
authors: Chinyere I
authors: CI
authors: Oarhe
authors: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors: Vinh
authors: V
authors: Dang
authors: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan.
authors: MyTrang
authors: M
authors: Dang
authors: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
authors: Hang
authors: H
authors: Nguyen
authors: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
authors: Indiwari
authors: I
authors: Gopallawa
authors: Department of Pediatrics/Neonatology, Michigan State University, East Lansing, Michigan.
authors: Ira H
authors: IH
authors: Gewolb
authors: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors: Bruce D
authors: BD
authors: Uhal
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D002245:Carbon Dioxide / Q000378:metabolism; D002470:Cell Survival; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D005740:Gases; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000196:embryology*; D010100:Oxygen / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D005740:Gases; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C099410:TAPI-2; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D002245:Carbon Dioxide; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D010100:Oxygen