Lee, Myong Jin Kim, Jeong Won Yang, Eun Gyeong 2024-01-20T19:05:01Z 2024-01-20T19:05:01Z 2021-09-02 2010-05-28 0006-291X https://pubs.kist.re.kr/handle/201004/131436 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. English ACADEMIC PRESS INC ELSEVIER SCIENCE GENE-EXPRESSION IRON CHELATOR OXYGEN ANGIOGENESIS HIF-1-ALPHA HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA ALPHA CELLS ERYTHROPOIETIN STABILIZATION Hinokitiol activates the hypoxia-inducible factor (HIF) pathway through inhibition of HIF hydroxylases Article 10.1016/j.bbrc.2010.04.099 1 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.396, no.2, pp.370 - 375 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 396 2 370 375 scie scopus 000278658000033 2-s2.0-77952745235 Biochemistry & Molecular Biology Biophysics Biochemistry & Molecular Biology Biophysics Article GENE-EXPRESSION IRON CHELATOR OXYGEN ANGIOGENESIS HIF-1-ALPHA HYPOXIA-INDUCIBLE-FACTOR-1-ALPHA ALPHA CELLS ERYTHROPOIETIN STABILIZATION Hypoxia-inducible factor Prolyl-4-hydroxylase Factor-inhibiting HIF-1 alpha Vascular endothelial growth factor Hinokitiol