Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Factor-inhibiting hypoxia-inducible factor (HIF)-1 (FIH-1) is an asparaginyl β-hydroxylase enzyme that was initially found to hydroxylate the HIF-α, preventing its transcriptional activity and leading to adaptive responses to hypoxia. More recently, other substrates, such as neurogenic locus notch homolog (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulation was never investigated. Given the key function of Notch in angiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells. We report that FIH-1 silencing in HUVECs results in reduced growth and increased apoptosis. The knockdown of FIH is associated with increased Notch2 activity, leading to enhanced expression of the Notch target hairy/enhancer-of-split related with YRPW motif protein 1 (Hey-1). Consistent with recent findings showing that Notch2 suppresses survivin (a key inhibitor of apoptosis), FIH targeting in HUVECs leads to selective repression of survivin in endothelial cells, thus promoting cell apoptosis and growth arrest. Our data support the concept that FIH-1 may interact with Notch2 and repress its activity, thereby playing a critical role in controlling the survival of vascular endothelial cells. These findings might pave the way toward novel, antiangiogenic strategies in disorders that are characterized by excessive vascular growth, such as cancer and rheumatoid arthritis.

Original publication

DOI

10.1096/fj.14-252379

Type

Journal article

Journal

FASEB J

Publication Date

07/2015

Volume

29

Pages

2814 - 2827

Keywords

Notch2, angiogenesis, apoptosis, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle Proteins, Cell Hypoxia, Cell Proliferation, Cell Survival, Endothelial Cells, Gene Knockdown Techniques, Human Umbilical Vein Endothelial Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Inhibitor of Apoptosis Proteins, Mixed Function Oxygenases, RNA Interference, RNA, Messenger, Receptor, Notch2, Repressor Proteins, Signal Transduction