title: Pathogenic cycle between the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine and the leukocyte-derived hemoprotein myeloperoxidase.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Interventional Cardiology, Hamburg University Heart Center, Hamburg, Germany.
authors.forename: Eike-Christin
authors.initials: EC
authors.lastname: von Leitner
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
authors.forename: Dorothee
authors.initials: D
authors.lastname: Atzler
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Slocum
authors.forename: Natalie
authors.initials: N
authors.lastname: Lund
authors.forename: Jan T
authors.initials: JT
authors.lastname: Kielstein
authors.forename: Renke
authors.initials: R
authors.lastname: Maas
authors.forename: Robin
authors.initials: R
authors.lastname: Schmidt-Haupt
authors.forename: Michaela
authors.initials: M
authors.lastname: Pekarova
authors.forename: Olaf
authors.initials: O
authors.lastname: Hellwinkel
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Louis G
authors.initials: LG
authors.lastname: D'Alecy
authors.forename: Denise
authors.initials: D
authors.lastname: Lau
authors.forename: Stephan
authors.initials: S
authors.lastname: Willems
authors.forename: Lukas
authors.initials: L
authors.lastname: Kubala
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Thomas
authors.initials: T
authors.lastname: Meinertz
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Gadegbeku
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Karsten
authors.initials: K
authors.lastname: Sydow
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors*; D009195:Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D009195:Peroxidase; D052250:Nitric Oxide Synthase Type III; D000581:Amidohydrolases; C059999:dimethylargininase