[HTML][HTML] 3-Hydroxypyruvate destabilizes hypoxia inducible factor and induces angiostasis
Investigative Ophthalmology & Visual Science, 2018•iovs.arvojournals.org
Purpose: Transcriptional analysis of retina protected by hypoxia-inducible factor (HIF)
stabilization demonstrates an increase in genes associated with aerobic glycolysis. We
hypothesized that since protection is associated with a change in metabolism, oxygen-
induced metabolites might transduce oxygen toxicity. We used global metabolic profiling to
identify retinal metabolites increased in hyperoxia compared to normoxia. Methods:
Untargeted gas chromatography mass spectroscopy (GC-MS) was performed on both …
stabilization demonstrates an increase in genes associated with aerobic glycolysis. We
hypothesized that since protection is associated with a change in metabolism, oxygen-
induced metabolites might transduce oxygen toxicity. We used global metabolic profiling to
identify retinal metabolites increased in hyperoxia compared to normoxia. Methods:
Untargeted gas chromatography mass spectroscopy (GC-MS) was performed on both …
Abstract
Purpose: Transcriptional analysis of retina protected by hypoxia-inducible factor (HIF) stabilization demonstrates an increase in genes associated with aerobic glycolysis. We hypothesized that since protection is associated with a change in metabolism, oxygen-induced metabolites might transduce oxygen toxicity. We used global metabolic profiling to identify retinal metabolites increased in hyperoxia compared to normoxia.
Methods: Untargeted gas chromatography mass spectroscopy (GC-MS) was performed on both mouse retina samples collected in hyperoxia and on primary human retinal endothelial cells, each with and without HIF stabilization. After identifying 3-hydropxypyruvate (3OH-pyruvate) as a unique hyperoxic metabolite, endothelial cells in culture and choroidal explants were challenged with 3OH-pyruvate in order to determine how this glycolytic intermediate was metabolized, and whether it had an effect on angiogenesis.
Results: 3OH-pyruvate was one of five metabolites at least 2.0-fold elevated in hyperoxia with a P value< 0.1. Once metabolized by endothelial cells, 3OH-pyruvate led to a 20-fold increase in 3-phosphoglycerate and a 4-fold increase in serine when cells were treated with Roxadustat to induce HIF stabilization. 3OH-pyruvate, but not pyruvate, destabilized HIF in endothelial cells with an increase in proline hydroxylation. 3OH-pyruvate was angiostatic in choroidal explant assays.
Conclusions: 3OH-pyruvate is a unique metabolite induced by hyperoxia that destabilizes HIF at least in part by a canonical pathway. 3OH-pyruvate induces angiostasis in vitro. HIF stabilization increases serine biosynthesis in vitro and in vivo.
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