Guanine Nitration in Idiopathic Pulmonary Fibrosis and Its Implication for Carcinogenesis

Terasaki, Yasuhiro; Akuta, Teruo; Terasaki, Mika; Sawa, Tomohiro; Mori, Takeshi; Okamoto, Tatsuya; Ozaki, Masakazu; Takeya, Motohiro; Akaike, Takaaki

doi:10.1164/rccm.200510-1580oc

Cited by 44 publications

(31 citation statements)

References 38 publications

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“…More important, we recently observed that excessive production of NO mediates guanine nitration in influenza virus-infected mouse lung (10). Nitration of guanine and/or guanosine in an environment in which NO is produced was also recently verified in other inflammatory lung diseases in humans (17). We reported in our recent study that, among several derivatives of 8-nitroguanine, 8-nitro-cGMP was the major product in biological systems and possessed certain unique features such as electrophilic, redox active, and cell signaling potentials (20).…”

Section: Discussionmentioning

confidence: 80%

“…RNS-induced nitration is known to occur not only with amino acids and proteins but also with nucleic acids. For example, formation of 8-nitroguanine or 8-nitroguanosine and their derivatives has been observed both in vitro and in vivo (13)(14)(15)(16)(17). 8-Nitroguanosine has a redox active property (18,19), which suggests that nucleotide nitration may have a biological function rather than simply being a biological marker.…”

Section: N Itric Oxide Produced By Inducible No Synthase (Inos)mentioning

confidence: 99%

“…Immunostaining was achieved by using biotin-conjugated monoclonal mouse Abs for 8-nitro-cGMP (clones 1G6 and 1H7) and by using rabbit polyclonal anti-HO-1 IgG (Stressgen Biotechnologies), as reported in a recent publication (17,20). For immunofluorescence staining for 8-nitro-cGMP, Abs were labeled with Alexa Fluor 555 (Molecular Probes-Invitrogen).…”

Section: Immunohistochemistry and Immunocytochemistrymentioning

confidence: 99%

See 2 more Smart Citations

Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis

Zaki

Fujii

Okamoto

et al. 2009

The Journal of Immunology

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Signaling mechanisms of NO-mediated host defense are yet to be elucidated. In this study, we report a unique signal pathway for cytoprotection during Salmonella infection that involves heme oxygenase 1 (HO-1) induced by a nitrated cyclic nucleotide, 8-nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP). Wild-type C57BL/6 mice and C57BL/6 mice lacking inducible NO synthase (iNOS) were infected with Salmonella enterica serovar Typhimurium LT2. HO-1 was markedly up-regulated during the infection, the level being significantly higher in wild-type mice than in iNOS-deficient mice. HO-1 up-regulation was associated with 8-nitro-cGMP formation detected immunohistochemically in Salmonella-infected mouse liver and peritoneal macrophages. 8-Nitro-cGMP either exogenously added or formed endogenously induced HO-1 in cultured macrophages infected with Salmonella. HO-1 inhibition by polyethylene glycol-conjugated zinc-protoporphyrin IX impaired intracellular killing of bacteria in mouse liver and in both RAW 264 cells and peritoneal macrophages. Infection-associated apoptosis was also markedly increased in polyethylene glycol-conjugated zinc-protoporphyrin IX-treated mouse liver cells and cultured macrophages. This effect of HO-1 inhibition was further confirmed by using HO-1 short interfering RNA in peritoneal macrophages. Our results suggest that HO-1 induced by NO-mediated 8-nitro-cGMP formation contributes, via its potent cytoprotective function, to host defense during murine salmonellosis.

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Section: Discussionmentioning

confidence: 80%

Section: N Itric Oxide Produced By Inducible No Synthase (Inos)mentioning

confidence: 99%

Section: Immunohistochemistry and Immunocytochemistrymentioning

confidence: 99%

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Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis

Zaki

Fujii

Okamoto

et al. 2009

The Journal of Immunology

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“…Synthesis of Various Guanine Nucleotides-Authentic 8-nitro-cGMP labeled or unlabeled with a stable isotope (8)(9)(10)(11)(12)(13)(14)(15) NO 2 -cGMP and 8-14 NO 2 -cGMP, respectively) was prepared according to the method we reported previously (10). 15 (9).…”

Section: Methodsmentioning

confidence: 99%

The Critical Role of Nitric Oxide Signaling, via Protein S-Guanylation and Nitrated Cyclic GMP, in the Antioxidant Adaptive Response

Fujii

Sawa

Ihara

et al. 2010

Journal of Biological Chemistry

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136

194

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A nitrated guanine nucleotide, 8-nitroguanosine 3,5-cyclic monophosphate (8-nitro-cGMP), is formed via nitric oxide (NO) and causes protein S-guanylation. However, intracellular 8-nitro-cGMP levels and mechanisms of formation of 8-nitrocGMP and S-guanylation are yet to be identified. In this study, we precisely quantified NO-dependent formation of 8-nitrocGMP in C6 glioma cells via liquid chromatography-tandem mass spectrometry. Treatment of cells with S-nitroso-Nacetylpenicillamine led to a rapid, transient increase in cGMP, after which 8-nitro-cGMP increased linearly up to a peak value comparable with that of cGMP at 24 h and declined thereafter. Markedly high levels (>40 M) of 8-nitro-cGMP were also evident in C6 cells that had been stimulated to express inducible NO synthase with excessive NO production. The amount of 8-nitro-cGMP generated was comparable with or much higher than that of cGMP, whose production profile slightly preceded 8-nitro-cGMP formation in the activated inducible NO synthase-expressing cells. These unexpectedly large amounts of 8-nitro-cGMP suggest that GTP (a substrate of cGMP biosynthesis), rather than cGMP per se, may undergo guanine nitration. Also, 8-nitro-cGMP caused S-guanylation of KEAP1 in cells, which led to Nrf2 activation and subsequent induction of antioxidant enzymes, including heme oxygenase-1; thus, 8-nitro-cGMP protected cells against cytotoxic effects of hydrogen peroxide. Proteomic analysis for endogenously modified KEAP1 with matrix-assisted laser desorption/ionization time-of-flighttandem mass spectrometry revealed that 8-nitro-cGMP S-guanylated the Cys 434 of KEAP1. The present report is therefore the first substantial corroboration of the biological significance of cellular 8-nitro-cGMP formation and potential roles of 8-nitro-cGMP in the Nrf2-dependent antioxidant response.Nitric oxide (NO) plays diverse physiological roles in vascular regulation, neuronal transmission, inflammation, and host defense against microbial pathogens. In vascular and neuronal systems, NO performs these functions mainly through a cGMPdependent mechanism (1, 2), but the presence and contribution of other pathways that are not directly linked to cGMP have also been suggested to operate in certain aspects of NO signaling occurring in various cells and tissues in different organisms (3-5). Among these other mechanisms is chemical modification of biomolecules, including nitrosylation and nitration of amino acids, proteins, and lipids, this modification being induced by NO-derived reactive nitrogen oxide species (RNOS), 3 such as peroxynitrite (ONOO Ϫ ) and nitrogen dioxide (NO 2 ) (3-5).RNOS cause nitration of nucleic acids in addition to amino acids, proteins, and lipids. We previously found that nitrated guanine derivatives, including 8-nitroguanine and 8-nitroguanosine, formed in cultured cells and in tissues from murine viral pneumonia and human lung disease (6 -8). An important finding was that 8-nitroguanosine possessed a unique redox activity, which suggested a critical biological rol...

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“…Because 8-nitro-cGMP is colocalized with mitochondria under certain circumstances (36,42), 8-nitro-cGMP may participate in regulating mitochondrial redox signaling, possibly by induction of protein S-guanylation. In this study, we developed a proteomic method-S-guanylation proteomicsto identify protein targets for S-guanylation in mitochondria.…”

Section: Innovationmentioning

confidence: 99%

S-guanylation proteomics for redox-based mitochondrial signaling

Sawa¹,

Rahaman²,

Ahtesham³

et al. 2012

Nitric Oxide

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Aims: 8-nitroguanosine 3¢,5¢-cyclic monophosphate (8-Nitro-cGMP) is a nitrated derivative of cGMP that is formed via cross-talk of reactive oxygen species formed by NADPH oxidase 2 and mitochondria. This nitrated nucleotide can function as a unique electrophilic second messenger in regulation of redox signaling by inducing a post-translational modification of protein thiols via cGMP adduction (protein S-guanylation). With S-guanylation proteomics, we investigated endogenous mitochondrial protein S-guanylation. Results: We developed a new mass spectrometry (MS)-based proteomic method-S-guanylation proteomics-which comprised two approaches: (i) direct protein digestion followed by immunoaffinity capture of S-guanylated peptides that were subjected to liquid chromatography-tandem MS (LC-MS/MS); and (ii) two-dimensional (2D)-gel electrophoretic separation of S-guanylated proteins that were subjected to in-gel digestion, followed by LC-MS/MS. We thereby identified certain mitochondrial proteins that are S-guanylated endogenously during immunological stimulation, including mortalin and 60-kDa heat-shock protein (HSP60). Mortalin and HSP60 were recently reported to regulate mitochondrial permeability-transition pore (mPTP) opening, at least partly, by interacting with cyclophilin D, an mPTP component. Our data revealed that immunological stimulation and 8-nitro-cGMP treatment induced mPTP opening in a cyclophilin D-dependent manner. Innovation and Conclusion: Our S-guanylation proteomic method determined that mitochondrial HSPs may be novel targets for redox modification via protein S-guanylation that participates in mPTP regulation and mitochondrial redox signaling. Antioxid. Redox Signal. 20, 295-307.

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Guanine Nitration in Idiopathic Pulmonary Fibrosis and Its Implication for Carcinogenesis

Cited by 44 publications

References 38 publications

Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis

Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis

The Critical Role of Nitric Oxide Signaling, via Protein S-Guanylation and Nitrated Cyclic GMP, in the Antioxidant Adaptive Response

S-guanylation proteomics for redox-based mitochondrial signaling

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