Document Detail

Nox2 NADPH oxidase has a critical role in insulin resistance-related endothelial cell dysfunction.
MedLine Citation:
PMID:  23349484     Owner:  NLM     Status:  MEDLINE    
Insulin resistance is characterized by excessive endothelial cell generation of potentially cytotoxic concentrations of reactive oxygen species. We examined the role of NADPH oxidase (Nox) and specifically Nox2 isoform in superoxide generation in two complementary in vivo models of human insulin resistance (endothelial specific and whole body). Using three complementary methods to measure superoxide, we demonstrated higher levels of superoxide in insulin-resistant endothelial cells, which could be pharmacologically inhibited both acutely and chronically, using the Nox inhibitor gp91ds-tat. Similarly, insulin resistance-induced impairment of endothelial-mediated vasorelaxation could also be reversed using gp91ds-tat. siRNA-mediated knockdown of Nox2, which was specifically elevated in insulin-resistant endothelial cells, significantly reduced superoxide levels. Double transgenic mice with endothelial-specific insulin resistance and deletion of Nox2 showed reduced superoxide production and improved vascular function. This study identifies Nox2 as the central molecule in insulin resistance-mediated oxidative stress and vascular dysfunction. It also establishes pharmacological inhibition of Nox2 as a novel therapeutic target in insulin resistance-related vascular disease.
Piruthivi Sukumar; Hema Viswambharan; Helen Imrie; Richard M Cubbon; Nadira Yuldasheva; Matthew Gage; Stacey Galloway; Anna Skromna; Parkavi Kandavelu; Celio X Santos; V Kate Gatenby; Jessica Smith; David J Beech; Stephen B Wheatcroft; Keith M Channon; Ajay M Shah; Mark T Kearney
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Diabetes     Volume:  62     ISSN:  1939-327X     ISO Abbreviation:  Diabetes     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-05-24     Completed Date:  2013-08-02     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2130-4     Citation Subset:  AIM; IM    
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MeSH Terms
Acetylcholine / pharmacology
Cells, Cultured
Chromatography, High Pressure Liquid
Endothelial Cells / drug effects*
Insulin Resistance / genetics,  physiology*
Membrane Glycoproteins / genetics,  metabolism*
Mice, Knockout
NADPH Oxidase / genetics,  metabolism*
Polymerase Chain Reaction
Vasodilator Agents / pharmacology
Grant Support
G0901203//Medical Research Council; RG/08/011/25922//British Heart Foundation; RG/12/5/29576//British Heart Foundation; //British Heart Foundation; //Medical Research Council
Reg. No./Substance:
0/Membrane Glycoproteins; 0/Vasodilator Agents; EC protein, mouse; EC Oxidase; N9YNS0M02X/Acetylcholine
Comment In:
Diabetes. 2013 Dec;62(12):e30   [PMID:  24264410 ]
Diabetes. 2013 Dec;62(12):e31   [PMID:  24264411 ]
Diabetes. 2013 Jun;62(6):1818-20   [PMID:  23704524 ]

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