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Crosstalk between nitric oxide and hypoxia-inducible factor signaling pathways: an update

Authors Hendrickson M, Poyton R

Received 10 January 2015

Accepted for publication 6 March 2015

Published 18 June 2015 Volume 2015:5 Pages 147—161

DOI https://doi.org/10.2147/RRBC.S58280

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 5

Editor who approved publication: Professor Nikolay Dokholyan


Marina D Hendrickson, Robert O Poyton

Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA


Abstract: Hypoxia-inducible factor-1 (HIF-1) is responsible for cellular adaptations to hypoxia. While oxygen (O2) negatively regulates its stability, many other factors affect HIF-1 stability and activity, including nitric oxide (NO). NO derived from l-arginine and nitrite (NO2) could nitrosylate or nitrate HIF-1 and multiple proteins involved in HIF-1 regulation, and can allow HIF-1 to escape normoxic degradation. In turn, HIF-1 can increase NO production through multiple mechanisms, including increased inducible nitric oxide synthase (iNOS) expression and subunit 4-2 of cytochrome c oxidase (COX4-2) expression. There is therefore a high degree of crosstalk between HIF-1 and NO signaling. As such, many cellular responses to NO are mediated by HIF-1, and vice versa. This includes, but is not limited to, angiogenesis, apoptosis, senescence, and metabolic changes. These pathways all have important functions in normal physiology and when altered can contribute or, in some cases, lead to pathogenesis.

Keywords: HIF, nitric oxide, Cco/NO mitochondrial signaling, ROS/RNS, cancer

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