Hypoxia-inducible factors regulate human and rat cystathionine β-synthase gene expression

Biochem J. 2014 Mar 1;458(2):203-11. doi: 10.1042/BJ20131350.


Increased catalytic activity of CBS (cystathionine β-synthase) was recently shown to mediate vasodilation of the cerebral microcirculation, which is initiated within minutes of the onset of acute hypoxia. To test whether chronic hypoxia was a stimulus for increased CBS expression, U87-MG human glioblastoma and PC12 rat phaeochromocytoma cells were exposed to 1% or 20% O2 for 24-72 h. CBS mRNA and protein expression were increased in hypoxic cells. Hypoxic induction of CBS expression was abrogated in cells transfected with vector encoding shRNA targeting HIF (hypoxia-inducible factor) 1α or 2α. Exposure of rats to hypobaric hypoxia (0.35 atm; 1 atm=101.325 kPa) for 3 days induced increased CBS mRNA, protein and catalytic activity in the cerebral cortex and cerebellum, which was blocked by administration of the HIF inhibitor digoxin. HIF-binding sites, located 0.8 and 1.2 kb 5' to the transcription start site of the human CBS and rat Cbs genes respectively, were identified by ChIP assays. A 49-bp human sequence, which encompassed an inverted repeat of the core HIF-binding site, functioned as a hypoxia-response element in luciferase reporter transcription assays. Thus HIFs mediate tissue-specific CBS expression, which may augment cerebral vasodilation as an adaptive response to chronic hypoxia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Brain / blood supply
  • Cells, Cultured
  • Cystathionine beta-Synthase / biosynthesis*
  • Cystathionine beta-Synthase / genetics
  • Gene Expression Regulation, Enzymologic*
  • HEK293 Cells
  • Humans
  • Hypoxia, Brain / enzymology*
  • Hypoxia, Brain / genetics
  • Hypoxia, Brain / pathology
  • Hypoxia-Inducible Factor 1 / physiology
  • Male
  • PC12 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Tissue Distribution / genetics
  • Vasodilation / genetics


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • Cystathionine beta-Synthase