Drug-Mediated Intracellular Donation of Nitric Oxide Potently Inhibits 5-Lipoxygenase: A Possible Key to Future Antileukotriene Therapy
| Autor: | Ann-Kathrin Häfner, Jasmin Fettel, Estel.la Buscató, Isabelle V. Maucher, Juliana Heidler, Jessica Roos, Anja Vogel, Michael J. Parnham, Ilka Wittig, Camilla Brat, Ewgenij Proschak, Gerd Geisslinger, Marcus Peters, Kai Zacharowski, Thorsten J. Maier, Carmela Matrone, Nadine Hellmuth, Anja Urbschat, Dieter Steinhilber, Benita Sommer, Benjamin Kühn, René Blöcher, Matthias Piesche, Oliver Werz, Carlo Angioni |
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| Přispěvatelé: | Roos, J, Peters, M, Maucher, Iv, Kühn, B, Fettel, J, Hellmuth, N, Brat, C, Sommer, B, Urbschat, A, Piesche, M, Vogel, A, Proschak, E, Blöcher, R, Buscató, E, Häfner, Ak, Matrone, C, Werz, O, Heidler, J, Wittig, I, Angioni, C, Geisslinger, G, Parnham, Mj, Zacharowski, K, Steinhilber, D, Maier, Tj. |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Leukotrienes Physiology medicine.medical_treatment Clinical Biochemistry Pharmacology Nitric Oxide pulmonary inflammation Biochemistry Nitric oxide Mice Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound In vivo Journal Article medicine Animals Humans NO-donating NSAID Lipoxygenase Inhibitors cysteine Molecular Biology General Environmental Science Whole blood Mice Inbred BALB C Leukotriene Arachidonate 5-Lipoxygenase Aspirin Dose-Response Relationship Drug Molecular Structure biology Anti-Inflammatory Agents Non-Steroidal Nitrosylation nitrosylation Cell Biology Antileukotriene HEK293 Cells 030104 developmental biology chemistry Arachidonate 5-lipoxygenase biology.protein Leukotriene Antagonists General Earth and Planetary Sciences Female Intracellular |
| Zdroj: | Roos, J, Peters, M, Maucher, I V, Kühn, B, Fettel, J, Hellmuth, N, Brat, C, Sommer, B, Urbschat, A, Piesche, M, Vogel, A, Proschak, E, Blöcher, R, Buscato, E L, Häfner, A-K, Matrone, C, Werz, O, Heidler, J, Wittig, I, Angioni, C, Geisslinger, G, Parnham, M J, Zacharowski, K, Steinhilber, D & Maier, T J 2018, ' Drug-mediated intracellular donation of nitric oxide potently inhibits 5-lipoxygenase : a possible key to future anti-leukotriene therapy ', Antioxidants & Redox Signaling, vol. 28, no. 14, pp. 1265-1285 . https://doi.org/10.1089/ars.2017.7155 |
| ISSN: | 1557-7716 1523-0864 |
| Popis: | AIMS: 5-lipoxygenase (5-LO) is the key enzyme of leukotriene 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 non-steroidal 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 leukotriene 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. |
| Databáze: | OpenAIRE |
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