Nitric oxide and reactive oxygen species exert opposing effects on the stability of hypoxia inducible factor‐1α (HIF‐ 1α) in explants of human pial arteries

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Abstract
Hypoxia induces angiogenesis, partly through stabilization of hypoxia‐inducible factor‐1α (HIF‐ 1α), leading to transcription of pro‐angiogenic factors. Here we examined the regulation of HIF‐ 1α by hypoxia and nitric oxide (NO) in explants of human cerebrovascular smooth muscle cells. Cells were treated with NO donors under normoxic or hypoxic (2% O 2 ) conditions, followed by analysis of HIF‐1α protein levels. Treatment with the NO donor sodium nitroprusside reduced levels of HIF‐1α, whereas NO donors, NOC‐18 and S ‐nitrosoglutathione, increased HIF‐1α levels. SIN‐1, which releases both NO and superoxide (O 2 •¯), reduced HIF‐1α levels, suggesting that inhibitory NO donors may elicit effects through peroxynitrite (ONOO•¯). O 2 •¯ generation by xanthine/xanthine oxidase also reduced HIF‐1α levels, confirming an inhibitory role for reactive oxygen species (ROS). Furthermore, superoxide dismutase increased HIF‐1α levels, and the NO scavenger carboxy‐PTIO reversed HIF‐1α stabilization by NO donors. Effects on HIF‐1α levels correlated with vascular endothelial growth factor transcription but did not affect HIF‐1α transcription, as measured by RT‐PCR and luciferase‐reporter assays. The results indicate that HIF‐1α is stabilized by agents that produce NO and reduce ROS but destabilized by agents that increase ROS, including O 2 •¯ and ONOO•¯. Thus we propose that the effect of NO on HIF‐1α signaling is critically dependent on the form of NO and the physiological environment of the responding cell.
Funding Information
  • American Heart Association (9930218N)
  • National Institutes of Health (1R01 HL‐67351)

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