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

Naoharu Takano, Ying Jie Peng, Ganesh K. Kumar, Weibo Luo, Hongxia Hu, Larissa A. Shimoda, Makoto Suematsu, Nanduri R. Prabhakar, Gregg L. Semenza

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21 Citations (Scopus)

Abstract

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 hypoxiaresponse element in luciferase reporter transcription assays. Thus HIFsmediate tissue-specificCBSexpression, whichmay augment cerebral vasodilation as an adaptive response to chronic hypoxia.

Original languageEnglish
Pages (from-to)203-211
Number of pages9
JournalBiochemical Journal
Volume458
Issue number2
DOIs
Publication statusPublished - 2014 Mar 1

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Keywords

  • Cerebral circulation
  • Cystathionine β-synthase (CBS)
  • Hydrogen sulfide
  • Hypoxia-inducible factor (HIF)
  • Oxygen

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Takano, N., Peng, Y. J., Kumar, G. K., Luo, W., Hu, H., Shimoda, L. A., Suematsu, M., Prabhakar, N. R., & Semenza, G. L. (2014). Hypoxia-inducible factors regulate human and rat cystathionine â-synthase gene expression. Biochemical Journal, 458(2), 203-211. https://doi.org/10.1042/BJ20131350