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Drug-mediated intracellular donation of nitric oxide potently inhibits 5-lipoxygenase: a possible key to future antileukotriene therapy

dc.contributor.authorRoos, Jessica
dc.contributor.authorPeters, Marcus
dc.contributor.authorMaucher, Isabelle V.
dc.contributor.authorKühn, Benjamin
dc.contributor.authorFettel, Jasmin
dc.contributor.authorHellmuth, Nadine
dc.contributor.authorBrat, Camilla
dc.contributor.authorSommer, Benita
dc.contributor.authorUrbschat, Anja
dc.contributor.authorPiesche, Matthias
dc.contributor.authorVogel, Anja
dc.contributor.authorProschak, Ewgenij
dc.contributor.authorBlöcher, René
dc.contributor.authorBuscató, Estella
dc.contributor.authorHäfner, Ann-Kathrin
dc.contributor.authorMatrone, Carmela
dc.contributor.authorWerz, Oliver
dc.contributor.authorHeidler, Juliana
dc.contributor.authorWittig, Ilka
dc.contributor.authorAngioni, Carlo
dc.contributor.authorGeisslinger, Gerd
dc.contributor.authorParnham, Michael J.
dc.contributor.authorZacharowski, Kai D.
dc.contributor.authorSteinhilber, Dieter
dc.contributor.authorMaier, Thorsten J.
dc.date.accessioned2022-11-28T21:08:39Z
dc.date.available2022-11-28T21:08:39Z
dc.date.issued2018
dc.identifier.urihttp://repositorio.ucm.cl/handle/ucm/4170
dc.description.abstractAims: 5-Lipoxygenase (5-LO) is the key enzyme of leukotriene (LT) biosynthesis and is critically involved in a number of inflammatory diseases such as arthritis, gout, bronchial asthma, atherosclerosis, and cancer. Because 5-LO contains critical nucleophilic amino acids, which are sensitive to electrophilic modifications, we determined the consequences of a drug-mediated intracellular release of nitric oxide (NO) on 5-LO product formation by human granulocytes and on 5-LO-dependent pulmonary inflammation in vivo. Results: Clinically relevant concentrations of NO-releasing nonsteroidal anti-inflammatory drugs and other agents releasing NO intracellularly suppress 5-LO product synthesis in isolated human granulocytes via direct S-nitrosylation of 5-LO at the catalytically important cysteines 416 and 418. Furthermore, suppression of 5-LO product formation was observed in ionophore-stimulated human whole blood and in an animal model of pulmonary inflammation. Innovation: Here, we report for the first time that drugs releasing NO intracellularly are efficient 5-LO inhibitors in vitro and in vivo at least equivalent to approved 5-LO inhibitors. Conclusion: Our findings provide a novel mechanistic strategy for the development of a new class of drugs suppressing LT biosynthesis by site-directed nitrosylation. The results may also help to better understand the well-recognized anti-inflammatory clinically relevant actions of NO-releasing drugs. Furthermore, our study describes in detail a novel molecular mode of action of NO. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16: 293–296, 2012) with the following serving as open reviewers: Angel Lanas, Hartmut Kühn, Joan Clària, Orina Belton. Antioxid. Redox Signal. 28, 1265–1285.es_CL
dc.language.isoenes_CL
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 Chile*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/*
dc.sourceAntioxidants & Redox Signaling, 28(14), 1265-1285es_CL
dc.subjectPulmonary inflammationes_CL
dc.subjectNO-donating NSAIDses_CL
dc.subjectCysteineses_CL
dc.subjectNitrosylationes_CL
dc.titleDrug-mediated intracellular donation of nitric oxide potently inhibits 5-lipoxygenase: a possible key to future antileukotriene therapyes_CL
dc.typeArticlees_CL
dc.ucm.facultadFacultad de Medicinaes_CL
dc.ucm.indexacionScopuses_CL
dc.ucm.indexacionIsies_CL
dc.ucm.uriwww.liebertpub.com/doi/full/10.1089/ars.2017.7155es_CL
dc.ucm.doidoi.org/10.1089/ars.2017.7155es_CL


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Atribución-NoComercial-SinDerivadas 3.0 Chile
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