Asymmetrical dimethylarginine (ADMA) and coronary endothelial function in patients with coronary artery disease and mild hypercholesterolemia

Maas, Renke; Quitzau, Kurt; Schwedhelm, Edzard; Spieker, Lukas E.; Rafflenbeul, W.; Steenpass, Anna; Lüscher, Thomas F.; Böger, Rainer H.

doi:10.1016/j.atherosclerosis.2006.03.024

Cited by 37 publications

(22 citation statements)

References 46 publications

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“…Impaired NO synthesis in hypercholesterolemia has been linked to increased plasma concentrations of the endogenous NOS inhibitor ADMA, which have frequently but not consistently been observed in patients with hypercholesterolemia (29 ). In this respect, it is of interest to note that the present data are in line with a subgroup analysis of a study in patients with renal failure, which revealed a nonsignificant trend toward a lower NO synthesis rate in patients with familial hypercholesterolemia (30 ).…”

Section: Molecular Mechanismssupporting

confidence: 73%

Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide–Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia

et al. 2008

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BACKGROUND:Endothelial function is impaired in hypercholesterolemia and atherosclerosis. Based on mostly indirect evidence, this impairment is attributed to reduced synthesis or impaired biological activity of endothelium-derived nitric oxide (NO). It was the aim of this study to directly estimate and compare wholebody NO production in normo-and hypercholesterolemia by applying a nonradioactive stable isotope dilution technique in vivo.

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Section: Molecular Mechanismssupporting

confidence: 73%

Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide–Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia

et al. 2008

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“…Patients receiving diuretics had higher ADMA than those not on diuretics. Confirming some (42 ) but not all (36,(43)(44)(45)(46) pertinent earlier work, individuals treated with lipid-lowering drugs (97% statins) had lower ADMA than those untreated. The use of antiplatelet drugs was associated with lower ADMA.…”

Section: Discussionsupporting

confidence: 51%

Asymmetrical Dimethylarginine Independently Predicts Total and Cardiovascular Mortality in Individuals with Angiographic Coronary Artery Disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Meinitzer

Seelhorst²,

Wellnitz³

et al. 2007

Clinical Chemistry

207

123

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“…Therefore, derangement of the l ‐arginine/NO pathway and increased oxidative stress by ADMA have been considered important contributing factors in the development of endothelial dysfunction 13, 14, 15. Epidemiological investigations have shown that the increased plasma level of ADMA may predict cardiovascular events in patients 16, 17. Although the clinical efficacy of statin therapy in reducing cardiovascular mortality and morbidity has been well established by several clinical trials,1, 2 whether ADMA impairs the statin‐mediated benefit in EC dysfunction and cardiovascular diseases remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

Hsu

Zhao²,

Lin

et al. 2016

JAHA

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BackgroundAsymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered a risk factor for the pathogenesis of cardiovascular diseases. Simvastatin, a lipid‐lowering drug with other pleiotropic effects, has been widely used for treatment of cardiovascular diseases. However, little is known about the effect and underlying molecular mechanisms of ADMA on the effectiveness of simvastatin in the vascular system.Methods and ResultsWe conducted a prospective cohort study to enroll 648 consecutive patients with coronary artery disease for a follow‐up period of 8 years. In patients with plasma ADMA level ≥0.49 μmol/L (a cut‐off value from receiver operating characteristic curve), statin treatment had no significant effect on cardiovascular events. We also conducted randomized, controlled studies using in vitro and in vivo models. In endothelial cells, treatment with ADMA (≥0.5 μmol/L) impaired simvastatin‐induced nitric oxide (NO) production, endothelial NO synthase (eNOS) phosphorylation, and angiogenesis. In parallel, ADMA markedly increased the activity of NADPH oxidase (NOX) and production of reactive oxygen species (ROS). The detrimental effects of ADMA on simvastatin‐induced NO production and angiogenesis were abolished by the antioxidant, N‐acetylcysteine, NOX inhibitor, or apocynin or overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH‐2). Moreover, in vivo, ADMA administration reduced Matrigel plug angiogenesis in wild‐type mice and decreased simvastatin‐induced eNOS phosphorylation in aortas of apolipoprotein E–deficient mice, but not endothelial DDAH‐2‐overexpressed aortas.ConclusionsWe conclude that ADMA may trigger NOX‐ROS signaling, which leads to restricting the simvastatin‐conferred protection of eNOS activation, NO production, and angiogenesis as well as the clinical outcome of cardiovascular events.

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Asymmetrical dimethylarginine (ADMA) and coronary endothelial function in patients with coronary artery disease and mild hypercholesterolemia

Cited by 37 publications

References 46 publications

Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide–Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia

Simultaneous Assessment of Endothelial Function, Nitric Oxide Synthase Activity, Nitric Oxide–Mediated Signaling, and Oxidative Stress in Individuals with and without Hypercholesterolemia

Asymmetrical Dimethylarginine Independently Predicts Total and Cardiovascular Mortality in Individuals with Angiographic Coronary Artery Disease (The Ludwigshafen Risk and Cardiovascular Health Study)

Asymmetric Dimethylarginine Limits the Efficacy of Simvastatin Activating Endothelial Nitric Oxide Synthase

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