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 | Yun-Ling He, Ming-Ming Li, Li-Ying Wu, Tong Zhao, Yao Di, Xin Huang, Xue-Feng Ding, Kui-Wu Wu, Ming Fan, Ling-Ling Zhu |
Journal | Molecular medicine (Cambridge, Mass.)
(Mol Med)
Vol. 20
Pg. 590-600
(Feb 23 2015)
ISSN: 1528-3658 [Electronic] England |
PMID | 25333920
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Hypoxia-Inducible Factor 1, alpha Subunit
- Ketoglutaric Acids
- Protective Agents
- 5-hydroxymethylfurfural
- Furaldehyde
- Luciferases, Firefly
- Ascorbic Acid
|
Topics |
- Animals
- Ascorbic Acid
(pharmacology)
- Brain
(drug effects, metabolism)
- Furaldehyde
(analogs & derivatives, pharmacology)
- Hypoxia
(metabolism)
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Ketoglutaric Acids
(pharmacology)
- Kidney
(drug effects, metabolism)
- Luciferases, Firefly
(genetics)
- Mice, Inbred C57BL
- Mice, Transgenic
- PC12 Cells
- Protective Agents
(pharmacology)
- Protein Structure, Tertiary
(genetics)
- Rats
|