title: Enhanced hypoxia-inducible factor (HIF)-1α stability induced by 5-hydroxymethyl-2-furfural (5-HMF) contributes to protection against hypoxia.
abstract: We first reported the role of 5-hydroxymethyl-2-furfural (5-HMF) against hypoxia. Here, we studied the mechanism by using oxygen-dependent degradation domain (ODD)-Luc mice, which are a useful model to probe the stabilization of hypoxia-inducible factor 1α (HIF-1α). Compared with three other compounds that have been reported to have a role in stabilizing HIF-1α, 5-HMF caused stronger bioluminescence, which is indicative of HIF-1α stability in the brain and kidney of ODD-Luc mice. We further demonstrated that the HIF-1α protein accumulated in response to 5-HMF in the brains and kidneys of these mice, as well as in PC12 cells. Additionally, 5-HMF promoted the nuclear translocation of HIF-1α and the transcriptional activity of HIF-1, which was evaluated by detecting vascular endothelial growth factor (VEGF ) mRNA expression. These results suggest that 5-HMF stabilized HIF-1α and increased its activity. Considering the role of proline hydroxylases (PHDs) in negatively regulating HIF-1α stability, we explored whether 5-HMF interacts with the substrates and cofactors of PHDs, such as 2-oxoglutarate (2-OG), Fe(2+) and vitamin C (VC), which affects the activity of PHDs. The result revealed that 5-HMF did not interact with Fe(2+) or 2-OG but interacted with VC. This interaction was confirmed by subsequent experiments, in which 5-HMF entered into cells and reduced the VC content. The enhanced stability of HIF-1α by 5-HMF was reversed by VC supplementation, and the improved survival of mice caused by 5-HMF under hypoxia was abrogated by VC supplementation. Thus, we demonstrated for the first time that 5-HMF increases HIF-1α stability by reducing the VC content, which mediates the protection against hypoxia.
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Yun-Ling
authors.initials: YL
authors.lastname: He
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Li
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Wu
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Di
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Ding
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Kui-Wu
authors.initials: KW
authors.lastname: Wu
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.|Beijing Institute for Brain Disorders, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Cognitive Science, Beijing Institute of Basic Medical Sciences, Beijing, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005662:Furaldehyde / Q000031:analogs & derivatives* / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D049409:Luciferases, Firefly / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016716:PC12 Cells; D020011:Protective Agents / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; D020011:Protective Agents; C008046:5-hydroxymethylfurfural; D005662:Furaldehyde; D049409:Luciferases, Firefly; D001205:Ascorbic Acid