A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells

Anilkumar, Narayana, Jose, Gorka San, Sawyer, Iain, Santos, Celio X C, Sand, Claire, Brewer, Alison C., Warren, Derek and Shah, Ajay M. (2013) A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and involved in redox signaling in vascular cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 33 (4). e104-e112. ISSN 1079-5642

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Abstract

OBJECTIVE: Reactive oxygen species-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase proteins (Noxs) are involved in cell differentiation, migration, and apoptosis. Nox4 is unique among Noxs in being constitutively active, and its subcellular localization may therefore be particularly important. In this study, we identified and characterized a novel nuclear-localized 28-kDa splice variant of Nox4 in vascular cells. APPROACH AND RESULTS: Nox4 immunoreactivity was noted in the nucleus and nucleolus of vascular smooth muscle cells and multiple other cell types by confocal microscopy. Cell fractionation, sequence analyses, and siRNA studies indicated that the nuclear-localized Nox4 is a 28-kDa splice variant, Nox4D, which lacks putative transmembrane domains. Nox4D overexpression resulted in significant NADPH-dependent reactive oxygen species production as detected by several different methods and caused increased phosphorylation of extracellular-signal- regulated kinase1/2 and the nuclear transcription factor Elk-1. Overexpression of Nox4D could also induce DNA damage as assessed by γ-H2AX phosphorylation. These effects were inhibited by a single amino acid substitution in the Nox4D NADPH-binding region. CONCLUSIONS: Nox4D is a nuclear-localized and functionally active splice variant of Nox4 that may have important pathophysiologic effects through modulation of nuclear signaling and DNA damage.

Item Type:	Article
Uncontrolled Keywords:	nadph oxidase,nox4,nox4d,nucleus,reactive oxygen species,redox signaling,vascular
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	Pure Connector
Date Deposited:	23 Nov 2016 00:41
Last Modified:	22 Oct 2022 01:55
URI:	https://ueaeprints.uea.ac.uk/id/eprint/61455
DOI:	10.1161/ATVBAHA.112.300956

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