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iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53

Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress...

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Autores principales: Nakazawa, Harumasa, Chang, Kyungho, Shinozaki, Shohei, Yasukawa, Takashi, Ishimaru, Kazuhiro, Yasuhara, Shingo, Yu, Yong-Ming, Martyn, J. A. Jeevendra, Tompkins, Ronald. G., Shimokado, Kentaro, Kaneki, Masao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242494/
https://www.ncbi.nlm.nih.gov/pubmed/28099528
http://dx.doi.org/10.1371/journal.pone.0170391
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author Nakazawa, Harumasa
Chang, Kyungho
Shinozaki, Shohei
Yasukawa, Takashi
Ishimaru, Kazuhiro
Yasuhara, Shingo
Yu, Yong-Ming
Martyn, J. A. Jeevendra
Tompkins, Ronald. G.
Shimokado, Kentaro
Kaneki, Masao
author_facet Nakazawa, Harumasa
Chang, Kyungho
Shinozaki, Shohei
Yasukawa, Takashi
Ishimaru, Kazuhiro
Yasuhara, Shingo
Yu, Yong-Ming
Martyn, J. A. Jeevendra
Tompkins, Ronald. G.
Shimokado, Kentaro
Kaneki, Masao
author_sort Nakazawa, Harumasa
collection PubMed
description Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn)-induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-κB and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-κB and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S-nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-κB and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn-induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S-nitrosylation and acetylation and DNA-binding capacity of p65 NF-κB and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylation-dependent activation (acetylation) of p65 NF-κB. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury.
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spelling pubmed-52424942017-02-06 iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53 Nakazawa, Harumasa Chang, Kyungho Shinozaki, Shohei Yasukawa, Takashi Ishimaru, Kazuhiro Yasuhara, Shingo Yu, Yong-Ming Martyn, J. A. Jeevendra Tompkins, Ronald. G. Shimokado, Kentaro Kaneki, Masao PLoS One Research Article Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn)-induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-κB and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-κB and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S-nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-κB and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn-induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S-nitrosylation and acetylation and DNA-binding capacity of p65 NF-κB and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylation-dependent activation (acetylation) of p65 NF-κB. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury. Public Library of Science 2017-01-18 /pmc/articles/PMC5242494/ /pubmed/28099528 http://dx.doi.org/10.1371/journal.pone.0170391 Text en © 2017 Nakazawa et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nakazawa, Harumasa
Chang, Kyungho
Shinozaki, Shohei
Yasukawa, Takashi
Ishimaru, Kazuhiro
Yasuhara, Shingo
Yu, Yong-Ming
Martyn, J. A. Jeevendra
Tompkins, Ronald. G.
Shimokado, Kentaro
Kaneki, Masao
iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53
title iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53
title_full iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53
title_fullStr iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53
title_full_unstemmed iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53
title_short iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53
title_sort inos as a driver of inflammation and apoptosis in mouse skeletal muscle after burn injury: possible involvement of sirt1 s-nitrosylation-mediated acetylation of p65 nf-κb and p53
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242494/
https://www.ncbi.nlm.nih.gov/pubmed/28099528
http://dx.doi.org/10.1371/journal.pone.0170391
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