An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes

Böger, Rainer H.; Bode‐Böger, Stefanie M.; Tsao, Philip S.; Lin, Patrick S.; Chan, Jason R.; Cooke, John P.

doi:10.1016/s0735-1097(00)01013-5

Cited by 212 publications

(162 citation statements)

References 52 publications

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“…The latter effect can be abolished by antioxidant strategies, which supports the concept that oxidative stress could be linked to the development of impaired vascular function in these patients. Incubation of endothelial cells with ADMA also increased formation of superoxide anions [35]. Consistently, short-term oral supplementation with ascorbic acid was able to improve endothelium-dependent vasodilatation in women with GDM [36].…”

Section: Discussionsupporting

confidence: 52%

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

Mittermayer

Meyer

et al. 2002

Diabetologia

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Aims/hypothesis. The concentration of asymmetrical dimethyl-L-arginine (ADMA), an endogenous inhibitor of the nitric oxide synthase, is increased in patients at risk or with cardiovascular disease. We have investigated ADMA concentrations in women with a history of gestational diabetes (GDM), who could develop endothelial dysfunction and Type II (non-insulin-dependent) diabetes mellitus after delivery, and in healthy control subjects. Methods. Previous GDM patients were grouped according to their BMI as obese (≥25 kg/m 2 , n=46) or non-adipose (<25 kg/m 2 , n=31). Serum samples were taken 14 to 16 weeks after delivery and after 1 year. The control group comprised 17 healthy women (BMI<25 kg/m 2 ). ADMA concentrations were analysed by high performance liquid chromatography. Results. ADMA concentrations were comparable between obese and non-adipose GDM patients (0.58±0.02 and 0.57±0.02 µmol/l, respectively), and higher than in the control group (0.47±0.03 µmol/l; p<0.006). Insulin resistance as estimated by the insulin sensitivity index was more frequent among the obese than the non-adipose GDM women (p<0.05) and control subjects (p<0.05, both). No change in ADMA concentrations was found after 1 year in women with GDM. There was only a slight correlation between ADMA and BMI (r=0.26, p<0.02), triglycerides (r=0.29, p<0.004), or fasting plasma glucose (r=0.21, p<0.05), and not with the insulin sensitivity index or other parameters. In a multiple regression analysis ADMA serum concentrations were only associated with triglycerides. Conclusion/interpretation. Circulating ADMA concentrations are increased in normoglycaemic women with previous GDM. This increase is independent from other risk factors or surrogate markers for diabetes or cardiovascular events. [Diabetologia (2002[Diabetologia ( ) 45:1372[Diabetologia ( -1378 Keywords Gestational diabetes, asymmetrical dimetylarginine, nitric oxide, insulin resistance, cholesterol. . L-arginine can also be methylated by intracellular methyltransferases [3], but the exact regulation of this pathway is not known. The methylated L-arginine metabolite, asymmetrical dimethyl-L-arginine (ADMA), inhibits the cellular L-arginine uptake and nitric oxide synthase activity in endothelial cells competitively [4]. The allosteric symmetrical dimethyl-L-arginine (SDMA) is produced in equivalent amounts, but is not a structural antagonist in nitric oxide synthesis [5].It has been speculated that accumulation of endogenous L-arginine metabolites and low availability of LNitric oxide is synthesized from the amino acid L-arginine by constitutive and inducible nitric oxide synthases [1] and plays an important role in the regulation

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Section: Discussionsupporting

confidence: 52%

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

Mittermayer

Meyer

et al. 2002

Diabetologia

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“…29 Furthermore, in the presence of ADMA, endothelial cells generate superoxide anion. 35 Accordingly, it seems reasonable to propose that CMV has multiple effects to impair endothelial NO bioactivity, for example, to induce expression of iNOS, to increase superoxide anion generation, to reduce DDAH activity, and thereby to increase ADMA elaboration.…”

Section: Attenuates Bioactive No In Vascular Cellsmentioning

confidence: 99%

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

et al. 2004

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Background-We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV. Methods and Results-Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion. Conclusions-CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway. (Circulation. 2004;109:500-505.)

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“…The bioavailability of L-arginine is determined by the relative concentrations of ADMA and L-arginine. L-Arginine deficiency leads to uncoupling of NOS and oxidant formation (Boger et al, 2000;. It is established that elevated ADMA contributes to endothelial dysfunction (Raptis et al, 2014), pulmonary inflammation (Klein et al, 2010), and fibrosis (Wells et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

Staab

Weigel

Xiao

et al. 2014

Journal of Immunotoxicology

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There is increasing evidence that the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethyl-arginine (ADMA) is involved in the pathogenesis of chronic lung diseases. One important regulator of this molecule is the ADMA-metabolizing enzyme dimethyl-arginine dimethyl-aminohydrolase (DDAH). The objective of this study was to determine whether perturbation of the ADMA-DDAH pathway contributes to lung inflammation following exposure to cigarette smoke (CS). For these studies, wild-type and DDAH transgenic mice were sham or CS-exposed. Serum ADMA levels were determined by mass spectrometry. ADMA content and DDAH expression were also visualized in mouse lung tissue by immunohistochemistry. DDAH expression was determined by real-time quantitative PCR (qPCR). Inflammation was assessed by H&E staining and analyses of total cell counts and fluid tumor necrosis factor (TNF)-levels (using ELISA) in lung lavage fluid. NF-B binding activity in mouse lung epithelial (LA-4) cells was assessed by a transcription factor-binding assay. The results indicated that the concentration of serum ADMA was increased following exposure to CS, and this corresponded with increased ADMA content in bronchial epithelial cells in lung tissue. Total lung DDAH expression was significantly decreased in lung tissue and cultured LA-4 cells following CS exposure. Addition of exogenous ADMA increased CSE-mediated NF-B binding activity and TNFa production in LA-4 cells more than 2-fold compared to that in CSE-exposed controls. CS-mediated lung inflammation was significantly attenuated in DDAH transgenic mice compared to in wild-type controls. These findings demonstrated that lung ADMA metabolism was altered in mice following CS exposure and suggested that ADMA played a role in CS-mediated inflammation through increasing the presence of inflammatory mediators in lung epithelial cells.

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An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes

Abstract: We concluded that the endogenous NO synthase inhibitor ADMA is synthesized in human endothelial cells. Asymmetric dimethylarginine increases endothelial oxidative stress and potentiates monocyte binding. Asymmetric dimethylarginine may be an endogenous proatherogenic molecule.

Cited by 212 publications

References 52 publications

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

Circulating concentrations of asymmetrical dimethyl- L -arginine are increased in women with previous gestational diabetes

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

Asymmetric dimethyl-arginine metabolism in a murine model of cigarette smoke-mediated lung inflammation

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