Hypoxia-inducible factors regulate human and rat cystathionine β-synthase gene expression.
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| 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 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.
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| Authors | Naoharu Takano, Ying-Jie Peng, Ganesh K Kumar, Weibo Luo, Hongxia Hu, Larissa A Shimoda, Makoto Suematsu, Nanduri R Prabhakar, Gregg L Semenza |
| Journal | The Biochemical journal (Biochem J) Vol. 458 Issue 2 Pg. 203-11 (Mar 01 2014) ISSN: 1470-8728 [Electronic] England |
| PMID | 24328859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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