期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 396, 期 2, 页码 370-375出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2010.04.099
关键词
Hypoxia-inducible factor; Prolyl-4-hydroxylase; Factor-inhibiting HIF-1 alpha; Vascular endothelial growth factor; Hinokitiol
资金
- Functional Proteomics Research Center of the 21st Century Frontier Research Program
- National Research Foundation of Korea [2009-0081531]
Hypoxia-inducible factor (HIF)-1 has been established as a master regulator of vascular responses to hypoxia and ischemia by driving transcriptional activation of angiogenic factors. Oxygen- and 2-oxoglutarate (2-OG)-dependent, iron(II) containing HIF-specific prolyl-4-hydroxylases (PHDs) and factor inhibiting HIF-1 alpha (FIH-1) catalyze the hydroxylation of the specific proline and asparagine residues of HIF-1 alpha, thereby controlling the level of HIF-1 alpha and ultimately the HIF response. Here, we unveil a new action of hinokitiol, an iron chelator found in natural plants, on stabilization of HIF-1 alpha in cell cultures in a dose-dependent manner. in vitro PHD2 and FIH activity assays based on fluorescence polarization reveal that such HIF-1 alpha stabilization is likely medicated by inhibitory effects of hinokitiol on prolyl and asparaginyl hydroxylation of HIF-1 alpha. In addition, the inhibition of PHD2 by hinokitiol is reversed by the addition of 2-OG and iron(II), suggesting that the underlying inhibitory mechanism involves displacement of 2-OG and a chelate formation with iron(II) at the enzyme active site by hinokitiol. Furthermore, hinokitiol treated cells show increased transcription of vascular endothelial growth factor, providing the therapeutic potential in the treatment of ischemic diseases. (C) 2010 Elsevier Inc. All rights reserved.
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