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Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice

We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and...

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Autores principales: Huang, An, Yang, Yang-Ming, Yan, Changdong, Kaley, Gabor, Hintze, Thomas H., Sun, Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501862/
https://www.ncbi.nlm.nih.gov/pubmed/22933112
http://dx.doi.org/10.2337/db12-0559
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author Huang, An
Yang, Yang-Ming
Yan, Changdong
Kaley, Gabor
Hintze, Thomas H.
Sun, Dong
author_facet Huang, An
Yang, Yang-Ming
Yan, Changdong
Kaley, Gabor
Hintze, Thomas H.
Sun, Dong
author_sort Huang, An
collection PubMed
description We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal–regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase–dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress–induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress–induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide–mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes.
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spelling pubmed-35018622013-12-01 Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice Huang, An Yang, Yang-Ming Yan, Changdong Kaley, Gabor Hintze, Thomas H. Sun, Dong Diabetes Signal Transduction We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular signal–regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase–dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress–induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress–induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide–mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes. American Diabetes Association 2012-12 2012-11-15 /pmc/articles/PMC3501862/ /pubmed/22933112 http://dx.doi.org/10.2337/db12-0559 Text en © 2012 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 Signal Transduction
Huang, An
Yang, Yang-Ming
Yan, Changdong
Kaley, Gabor
Hintze, Thomas H.
Sun, Dong
Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice
title Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice
title_full Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice
title_fullStr Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice
title_full_unstemmed Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice
title_short Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice
title_sort altered mapk signaling in progressive deterioration of endothelial function in diabetic mice
topic Signal Transduction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501862/
https://www.ncbi.nlm.nih.gov/pubmed/22933112
http://dx.doi.org/10.2337/db12-0559
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