Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase
| Autor: | Dimitrios Tsikas, Karsten Sydow, Jan T. Kielstein, Michaela Pekarova, Crystal A. Gadegbeku, Lukáš Kubala, Stefan Blankenberg, Renke Maas, Louis G. D'Alecy, Robin Schmidt-Haupt, Stephan Willems, Natalie Lund, Jessica L. Slocum, Denise Lau, Rainer H. Böger, Olaf J C Hellwinkel, Dorothee Atzler, Anna Klinke, Edzard Schwedhelm, Eike Christin Von Leitner, Thomas Meinertz, Stephan Baldus, Heimo Ehmke |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Nitric Oxide Synthase Type III Endothelium Neutrophils HL-60 Cells Mice Transgenic Inflammation In Vitro Techniques Pharmacology Arginine Nitric Oxide Amidohydrolases Mice Superoxides In vivo Physiology (medical) medicine Animals Humans Peroxidase Mice Knockout Dose-Response Relationship Drug ATP synthase biology business.industry Degranulation Mice Inbred C57BL Nitric oxide synthase Dose–response relationship medicine.anatomical_structure Biochemistry Cardiovascular Diseases Myeloperoxidase Models Animal biology.protein Female medicine.symptom Cardiology and Cardiovascular Medicine business Signal Transduction |
| Zdroj: | Circulation. 124:2735-2745 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.111.060541 |
| Popis: | Background— The nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) and the leukocyte-derived hemoprotein myeloperoxidase (MPO) are associated with cardiovascular diseases. Activation of monocytes and polymorphonuclear neutrophils (PMNs) with concomitant release of MPO is regulated in a nitric oxide–dependent fashion. The aim of the study was to investigate a potential 2-way interaction between ADMA and MPO. Methods and Results— Ex vivo, ADMA uptake by isolated human PMNs, the principal source of MPO in humans, significantly impaired nitric oxide synthase activity determined by gas chromatography–mass spectrometry. In humans, short-term ADMA infusion (0.0125 mg · kg −1 · min −1 ) significantly increased MPO plasma concentrations. Functionally, PMN exposure to ADMA enhanced leukocyte adhesion to endothelial cells, augmented NADPH oxidase activity, and stimulated PMN degranulation, resulting in release of MPO. In vivo, a 28-day ADMA infusion (250 μmol · kg −1 · d −1 ) in C57Bl/6 mice significantly increased plasma MPO concentrations, whereas this ADMA effect on MPO was attenuated by human dimethylarginine dimethylaminohydrolase1 (hDDAH1) overexpression. Moreover, the MPO-derived reactive molecule hypochlorous acid impaired recombinant hDDAH1 activity in vitro. In MPO −/− mice, the lipopolysaccharide-induced increase in systemic ADMA concentrations was abrogated. Conclusions— ADMA profoundly impairs nitric oxide synthesis of PMNs, resulting in increased PMN adhesion to endothelial cells, superoxide generation, and release of MPO. In addition, MPO impairs DDAH1 activity. Our data reveal an ADMA-induced cycle of PMN activation, enhanced MPO release, and subsequent impairment of DDAH1 activity. These findings not only highlight so far unrecognized cytokine-like properties of ADMA but also identify MPO as a regulatory switch for ADMA bioavailability under inflammatory conditions. |
| Databáze: | OpenAIRE |
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