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.
abstract: 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.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Nakazawa
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Chang
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Shinozaki
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yasukawa
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ishimaru
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yasuhara
authors.affiliation: Shriners Hospitals for Children, Boston, Massachusetts, United States of America.|Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yu
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: J A Jeevendra
authors.initials: JA
authors.lastname: Martyn
authors.affiliation: Shriners Hospitals for Children, Boston, Massachusetts, United States of America.|Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
authors.affiliation: Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shimokado
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America.|Shriners Hospitals for Children, Boston, Massachusetts, United States of America.
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002056:Burns / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1