Cargando…

Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction

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 res...

Descripción completa

Detalles Bibliográficos
Autores principales: Sukumar, Piruthivi, Viswambharan, Hema, Imrie, Helen, Cubbon, Richard M., Yuldasheva, Nadira, Gage, Matthew, Galloway, Stacey, Skromna, Anna, Kandavelu, Parkavi, Santos, Celio X., Gatenby, V. Kate, Smith, Jessica, Beech, David J., Wheatcroft, Stephen B., Channon, Keith M., Shah, Ajay M., Kearney, Mark T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661635/
https://www.ncbi.nlm.nih.gov/pubmed/23349484
http://dx.doi.org/10.2337/db12-1294
_version_ 1782270718108499968
author Sukumar, Piruthivi
Viswambharan, Hema
Imrie, Helen
Cubbon, Richard M.
Yuldasheva, Nadira
Gage, Matthew
Galloway, Stacey
Skromna, Anna
Kandavelu, Parkavi
Santos, Celio X.
Gatenby, V. Kate
Smith, Jessica
Beech, David J.
Wheatcroft, Stephen B.
Channon, Keith M.
Shah, Ajay M.
Kearney, Mark T.
author_facet Sukumar, Piruthivi
Viswambharan, Hema
Imrie, Helen
Cubbon, Richard M.
Yuldasheva, Nadira
Gage, Matthew
Galloway, Stacey
Skromna, Anna
Kandavelu, Parkavi
Santos, Celio X.
Gatenby, V. Kate
Smith, Jessica
Beech, David J.
Wheatcroft, Stephen B.
Channon, Keith M.
Shah, Ajay M.
Kearney, Mark T.
author_sort Sukumar, Piruthivi
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3661635
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-36616352014-06-01 Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction Sukumar, Piruthivi Viswambharan, Hema Imrie, Helen Cubbon, Richard M. Yuldasheva, Nadira Gage, Matthew Galloway, Stacey Skromna, Anna Kandavelu, Parkavi Santos, Celio X. Gatenby, V. Kate Smith, Jessica Beech, David J. Wheatcroft, Stephen B. Channon, Keith M. Shah, Ajay M. Kearney, Mark T. Diabetes Original Research 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. American Diabetes Association 2013-06 2013-05-17 /pmc/articles/PMC3661635/ /pubmed/23349484 http://dx.doi.org/10.2337/db12-1294 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Sukumar, Piruthivi
Viswambharan, Hema
Imrie, Helen
Cubbon, Richard M.
Yuldasheva, Nadira
Gage, Matthew
Galloway, Stacey
Skromna, Anna
Kandavelu, Parkavi
Santos, Celio X.
Gatenby, V. Kate
Smith, Jessica
Beech, David J.
Wheatcroft, Stephen B.
Channon, Keith M.
Shah, Ajay M.
Kearney, Mark T.
Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction
title Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction
title_full Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction
title_fullStr Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction
title_full_unstemmed Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction
title_short Nox2 NADPH Oxidase Has a Critical Role in Insulin Resistance–Related Endothelial Cell Dysfunction
title_sort nox2 nadph oxidase has a critical role in insulin resistance–related endothelial cell dysfunction
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661635/
https://www.ncbi.nlm.nih.gov/pubmed/23349484
http://dx.doi.org/10.2337/db12-1294
work_keys_str_mv AT sukumarpiruthivi nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT viswambharanhema nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT imriehelen nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT cubbonrichardm nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT yuldashevanadira nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT gagematthew nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT gallowaystacey nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT skromnaanna nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT kandaveluparkavi nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT santosceliox nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT gatenbyvkate nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT smithjessica nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT beechdavidj nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT wheatcroftstephenb nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT channonkeithm nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT shahajaym nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction
AT kearneymarkt nox2nadphoxidasehasacriticalroleininsulinresistancerelatedendothelialcelldysfunction