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. 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 ⅐ kg Ϫ1 ⅐ min Ϫ1 ) 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 mol ⅐ kg Ϫ1 ⅐ d Ϫ1 ) 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 Ϫ/Ϫ 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. (Circulation. 2011;124:2735-2745.)

Platelet hyperaggregability in patients with atrial fibrillation

“…The direct correlation currently documented between MPO and ADMA concentrations has previously been observed in vitro [14]. It was found that exposure of neutrophils to ADMA promoted neutrophil activation and degranulation; reciprocally, it was also observed that lipopolysaccharide infusion promoted plasma ADMA accumulation in wild-type mice, but not in MPO-null mice.…”

“…Previous research has identified a reciprocal relationship between ADMA, neutrophil activation, and MPO release [14]. Clinical correlations have also been established between plasma MPO and endothelial dysfunction [15].…”

Asymmetric dimethylarginine regulates the lipopolysaccharide-induced nitric oxide production in macrophages by suppressing the activation of NF-kappaB and iNOS expression

“…Immediately before the start of experiments, the cultivation media was replaced with fresh DMEM supplemented with 10% FBS. Macrophages were treated with different concentrations of methylarginines with/without combination of lipopolysaccharide (LPS) from Gram-negative bacteria (100 ng/ml, Escherichia coli serotype 026:B6) for 24 h. The concentrations of methylarginines were selected based on the previously published studies evaluating their effects on different types of cells (Closs et al, 1997;Chan et al, 2000;Fickling et al, 1999;Masuda, 2008;von Leitner et al, 2011).…”

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia

“…Based on these fi ndings, the positive correlations between the concentration of MPO and sCD40L, ADMA, sICAM-1 levels may highlight the role of polymorphonuclear leukocytes in the atherosclerotic process. Additionally, ADMA was found to impair nitric oxide synthesis of polymorphonuclear leukocytes, resulting in increased leukocyte adhesion to endothelial cells, superoxide generation, and MPO release [10]. The signifi cant association between MPO and ADMA levels may prove the ADMA/MPO interaction concept.…”

“…Previous data reveal an ADMA-induced cycle of polymorphonuclear leukocyte activation and enhanced MPO release. These fi ndings highlight the cytokine-like properties of ADMA and also identify MPO as a potential regulatory switch for ADMA bioavailability under infl ammatory conditions [10]. The CD40 Ligand (CD40L) is ubiquitously expressed on cell types that are implicated in infl ammato-…”