title: NOX1/NADPH oxidase is involved in endotoxin-induced cardiomyocyte apoptosis.
abstract: The functional significance of NOX1/NADPH oxidase in the heart has not been explored due to its low expression relative to other NOX homologs identified so far. We aimed to clarify the role of NOX1/NADPH oxidase in the septic heart by utilizing mice deficient in the Nox1 gene (Nox1(-/Y)). Sepsis was induced by intraperitoneal administration of lipopolysaccharides (LPS: 25mg/kg) or cecal ligation and puncture (CLP) surgery. A marked elevation of NOX1 mRNA was demonstrated in cardiac tissue, which was accompanied by increased production of reactive oxygen species (ROS). In Nox1(-/Y) treated with LPS, cardiac dysfunction and survival were significantly improved compared with wild-type mice (Nox1(+/Y)) treated with LPS. Concomitantly, LPS-induced cardiomyocyte apoptosis and activation of caspase-3 were alleviated in Nox1(-/Y). The level of phosphorylated Akt in cardiac tissue was significantly lowered in Nox1(+/Y) but not in Nox1(-/Y) treated with LPS or that underwent CLP surgery. Increased oxidation of cysteine residues of Akt and enhanced interaction of Akt with protein phosphatase 2A (PP2A), a major phosphatase implicated in the dephosphorylation of Akt, were demonstrated in LPS-treated Nox1(+/Y). These responses to LPS were significantly attenuated in Nox1(-/Y). Taken together, ROS derived from NOX1/NADPH oxidase play a pivotal role in endotoxin-induced cardiomyocyte apoptosis by increasing oxidation of Akt and subsequent dephosphorylation by PP2A. Marked up-regulation of NOX1 may affect the risk of mortality under systemic inflammatory conditions.
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Matsuno
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Misaki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Masato
authors.initials: M
authors.lastname: Katsuyama
authors.forename: Wenhao
authors.initials: W
authors.lastname: Cui
authors.forename: Ayumi
authors.initials: A
authors.lastname: Murata
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ibi
authors.forename: Kanako
authors.initials: K
authors.lastname: Ikami
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Denan
authors.initials: D
authors.lastname: Jin
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000150:complications / Q000276:immunology / Q000473:pathology; D015870:Gene Expression; D006333:Heart Failure / Q000276:immunology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000276:immunology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000276:immunology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C000614712:NOX1 protein, rat; C422943:Nox4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse