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Special Issue "ADMA and Nitrergic System"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (30 December 2013)

Special Issue Editors

Guest Editor
Dr. Graziano Riccioni

Studio Medico Polispecialistico, Via Magenta 106, San Severo, 71016 Foggia, Italy
Website | E-Mail
Fax: +39 882227022
Interests: atherosclerosis; statins; ivabradine; ischemic cardiac disease; antioxidants; endothelial dyfunction and metabolities; carotenoids
Guest Editor
Dr. Lorenza Speranza

Department of Medicine and Science of Aging, Applied Biology, “G. D’Annunzio” University, Chieti-Pescara, Italy
E-Mail
Fax: +39 0 8713554551
Interests: Oxidative stress; nitric oxide; nitric oxide synthase; natural compounds; asymmetric dimethylarginine; aging; brain natriuretic peptide; interleukin

Special Issue Information

Dear Colleagues,

Nitric oxide (NO) is one of the most important mediators synthesized from L-arginine by a family of NO synthases (NOS),  involved in the regulation of vascular tone, neurotransmission in the central and peripheral nervous system, and regulation of mitochondrial respiration. The availability of NO in a given cell depends on many factors including expression and activity of several NOS (neuronal, inducible, and endothelial), abundance of NOS substrate, L-arginine, and its cofactor, tetrahydrobiopterin. NO production may also be regulated by endogenous NOS inhibitors, in particular asymmetric dimethylarginine (ADMA), synthesized during the methylation of protein arginine residues by protein arginine. ADMA is a competitive inhibitor of NOS, decrease NO availability and is eliminated by renal excretion or metabolized by dimethylarginine dimethylaminohydrolases (DDAH) to citruline and dimethylamine. Two other endogenous methylarginines are also synthesized by protein-arginine methyltransferases (PRMT): N-monomethyl-L-arginine (L-NMMA) and symmetric dimethylarginine (SDMA).

Plasma concentration of ADMA is increased in patients with hyperlipidemia, diabetes mellitus, arterial hypertension, hyperhomocysteinemia, heart and chronic renal failure. The increased concentration of ADMA is positively correlated with markers of atherosclerosis, such as carotid artery intima-media thickness and has a predictive value for acute cardiovascular events.

There is no doubt that ADMA regulate NOS activity under physiological and pathological conditions, is increased in many diseases in which NO deficiency, is metabolized by the endothelium and may represent an important index of endothelial dysfunction. The possibility to modulate ADMA by pharmacotherapy is a new and important approach of many acute and chronic disease and is still of great interest. Some medication such angiotensin converting enzyme inhibitors and angiotensin AT1 receptor antagonists, fibrates, metformin, antioxidant vitamins, aspirin, n-3 polyunsaturated fatty acids and flavonoids are drugs and substances which have shown to reduce ADMA levels in humans with the improvement of NO synthesis. Agents modifying ADMA concentrations should be considered in the treatment of many chronic diseases.

Dr. Graziano Riccioni
Dr. Lorenza Speranza
Guest Editors

Submission

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Keywords

  • asymmetric dimethylarginine
  • nitric oxide; nitric oxide synthase
  • symmetric dimethylarginine
  • dimethylarginine dimethylaminohydrolases
  • N-monomethyl-L-arginine
  • protein-arginine methyltransferases
  • reactive oxygen species

Published Papers (17 papers)

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Editorial

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Open AccessEditorial Biological Functional Relevance of Asymmetric Dimethylarginine (ADMA) in Cardiovascular Disease
Int. J. Mol. Sci. 2013, 14(12), 24412-24421; doi:10.3390/ijms141224412
Received: 29 October 2013 / Revised: 5 December 2013 / Accepted: 6 December 2013 / Published: 16 December 2013
Cited by 11 | PDF Full-text (257 KB) | HTML Full-text | XML Full-text
Abstract
There is growing evidence that increased levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) may contribute to endothelial dysfunction. Studies in animal models as well as in humans have suggested that the increase in ADMA occurs at a time when vascular
[...] Read more.
There is growing evidence that increased levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) may contribute to endothelial dysfunction. Studies in animal models as well as in humans have suggested that the increase in ADMA occurs at a time when vascular disease has not yet become clinically evident. ADMA competitively inhibits NO elaboration by displacing L-arginine from NO synthase. In a concentration-dependent manner, it thereby interferes not only with endothelium-dependent, NO-mediated vasodilation, but also with other biological functions exerted by NO. The upshot may be a pro-atherogenic state. Recently, several studies have investigated the effect of various therapeutical interventions on ADMA plasma concentrations. [...] Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)

Research

Jump to: Editorial, Review, Other

Open AccessArticle ADMA/SDMA in Elderly Subjects with Asymptomatic Carotid Atherosclerosis: Values and Site-Specific Association
Int. J. Mol. Sci. 2014, 15(4), 6391-6398; doi:10.3390/ijms15046391
Received: 1 January 2014 / Revised: 2 March 2014 / Accepted: 10 March 2014 / Published: 15 April 2014
Cited by 7 | PDF Full-text (212 KB) | HTML Full-text | XML Full-text
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor known as a mediator of endothelial dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. We assessed the
[...] Read more.
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor known as a mediator of endothelial dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. We assessed the relationship between ADMA values and site-specific association of asymptomatic carotid atherosclerosis (intima-media thickness (CIMT) and plaque) in elderly subjects. One hundred and eighty subjects underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and carotid ultrasound investigation (CUI). All subjects had no acute or chronic symptoms of carotid atherosclerosis. Statistical analyses showed that high plasma levels of ADMA/SDMA were positively correlated to carotid atherosclerosis (CIMT and plaque) (p < 0.001), with significant site-specific association. Total cholesterol, low density lipoprotein cholesterol, triglycerides and C-reactive protein plasma concentrations were significantly associated with asymptomatic carotid atherosclerosis (p < 0.001). High serum concentrations of ADMA and SDMA were associated with carotid atherosclerotic lesions as measured by CIMT ad plaque and may represent a new marker of asymptomatic carotid atherosclerosis in elderly subjects. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Asymmetric Dimethylarginine in Chronic Obstructive Pulmonary Disease (ADMA in COPD)
Int. J. Mol. Sci. 2014, 15(4), 6062-6071; doi:10.3390/ijms15046062
Received: 30 December 2013 / Revised: 7 March 2014 / Accepted: 31 March 2014 / Published: 10 April 2014
Cited by 8 | PDF Full-text (428 KB) | HTML Full-text | XML Full-text
Abstract
l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma
[...] Read more.
l-Arginine metabolism including the nitric oxide (NO) synthase and arginase pathways is important in the maintenance of airways function. We have previously reported that accumulation of asymmetric dimethylarginine (ADMA) in airways, resulting in changes in l-arginine metabolism, contributes to airways obstruction in asthma and cystic fibrosis. Herein, we assessed l-arginine metabolism in airways of patients with chronic obstructive pulmonary disease (COPD). Lung function testing, measurement of fractional exhaled NO (FeNO) and sputum NO metabolites, as well as quantification of l-arginine metabolites (l-arginine, l-ornithine, l-citrulline, ADMA and symmetric dimethylarginine) using liquid chromatography-mass spectrometry (LC-MS) were performed. Concentrations of l-ornithine, the product of arginase activity, correlated directly with l-arginine and ADMA sputum concentrations. FeNO correlated directly with pre- and post-bronchodilator forced expiratory volume in one second (FEV1). Sputum arginase activity correlated inversely with total NO metabolite (NOx) and nitrite concentrations in sputum, and with pre- and post-bronchodilator FEV1. These findings suggest that ADMA in COPD airways results in a functionally relevant shift of l-arginine breakdown by the NO synthases towards the arginase pathway, which contributes to airway obstruction in these patients. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Effect of Lowering Asymmetric Dimethylarginine (ADMA) on Vascular Pathology in Atherosclerotic ApoE-Deficient Mice with Reduced Renal Mass
Int. J. Mol. Sci. 2014, 15(4), 5522-5535; doi:10.3390/ijms15045522
Received: 17 February 2014 / Revised: 18 March 2014 / Accepted: 24 March 2014 / Published: 31 March 2014
PDF Full-text (551 KB) | HTML Full-text | XML Full-text
Abstract
The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n =
[...] Read more.
The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n = 39) and C57Bl/6J wild-type littermates (WT, n = 27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n = 11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Exogenous Asymmetric Dimethylarginine (ADMA) in Pathogenesis of Ischemia-Reperfusion-Induced Gastric Lesions: Interaction with Protective Nitric Oxide (NO) and Calcitonin Gene-Related Peptide (CGRP)
Int. J. Mol. Sci. 2014, 15(3), 4946-4964; doi:10.3390/ijms15034946
Received: 27 December 2013 / Revised: 3 March 2014 / Accepted: 4 March 2014 / Published: 20 March 2014
Cited by 7 | PDF Full-text (1012 KB) | HTML Full-text | XML Full-text
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated
[...] Read more.
Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) synthesis inhibitor and pro-inflammatory factor. We investigated the role of ADMA in rat gastric mucosa compromised through 30 min of gastric ischemia (I) and 3 h of reperfusion (R). These I/R animals were pretreated with ADMA with or without the combination of l-arginine, calcitonin gene-related peptide (CGRP) or a small dose of capsaicin, all of which are known to afford protection against gastric lesions, or with a farnesoid X receptor (FXR) agonist, GW 4064, to increase the metabolism of ADMA. In the second series, ADMA was administered to capsaicin-denervated rats. The area of gastric damage was measured with planimetry, gastric blood flow (GBF) was determined by H2-gas clearance, and plasma ADMA and CGRP levels were determined using ELISA and RIA. ADMA significantly increased I/R-induced gastric injury while significantly decreasing GBF, the luminal NO content, and the plasma level of CGRP. This effect of ADMA was significantly attenuated by pretreatment with CGRP, l-arginine, capsaicin, or a PGE2 analogue. In GW4064 pretreated animals, the I/R injury was significantly reduced and this effect was abolished by co-treatment with ADMA. I/R damage potentiated by ADMA was exacerbated in capsaicin-denervated animals with a further reduction of CGRP. Plasma levels of IL-10 were significantly decreased while malonylodialdehyde (MDA) and plasma TNF-α contents were significantly increased by ADMA. In conclusion, ADMA aggravates I/R-induced gastric lesions due to a decrease of GBF, which is mediated by a fall in NO and CGRP release, and the enhancement of lipid peroxidation and its pro-inflammatory properties. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Endogenous Nitric-Oxide Synthase Inhibitor ADMA after Acute Brain Injury
Int. J. Mol. Sci. 2014, 15(3), 4088-4103; doi:10.3390/ijms15034088
Received: 30 December 2013 / Revised: 14 February 2014 / Accepted: 3 March 2014 / Published: 6 March 2014
Cited by 2 | PDF Full-text (5811 KB) | HTML Full-text | XML Full-text
Abstract
Previous results on nitric oxide (NO) metabolism after traumatic brain injury (TBI) show variations in NO availability and controversial effects of exogenous nitric oxide synthase (NOS)-inhibitors. Furthermore, elevated levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) were reported in cerebro-spinal fluid (CSF)
[...] Read more.
Previous results on nitric oxide (NO) metabolism after traumatic brain injury (TBI) show variations in NO availability and controversial effects of exogenous nitric oxide synthase (NOS)-inhibitors. Furthermore, elevated levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) were reported in cerebro-spinal fluid (CSF) after traumatic subarachnoid hemorrhage (SAH). Therefore, we examined whether ADMA and the enzymes involved in NO- and ADMA-metabolism are expressed in brain tissue after TBI and if time-dependent changes occur. TBI was induced by controlled cortical impact injury (CCII) and neurological performance was monitored. Expression of NOS, ADMA, dimethylarginine dimethylaminohydrolases (DDAH) and protein-arginine methyltransferase 1 (PRMT1) was determined by immunostaining in different brain regions and at various time-points after CCII. ADMA and PRMT1 expression decreased in all animals after TBI compared to the control group, while DDAH1 and DDAH2 expression increased in comparison to controls. Furthermore, perilesionally ADMA is positively correlated with neuroscore performance, while DDAH1 and DDAH2 are negatively correlated. ADMA and its metabolizing enzymes show significant temporal changes after TBI and may be new targets in TBI treatment. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessCommunication Clinical Evaluation of Extracellular ADMA Concentrations in Human Blood and Adipose Tissue
Int. J. Mol. Sci. 2014, 15(1), 1189-1200; doi:10.3390/ijms15011189
Received: 10 December 2013 / Revised: 7 January 2014 / Accepted: 8 January 2014 / Published: 17 January 2014
Cited by 3 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text
Abstract
Circulating asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, has been proposed as a biomarker for clinical outcome. Dimethylarginine dimethylaminohydrolase (DDAH) is the main enzyme responsible for ADMA metabolism and elimination. Adipose tissue ADMA concentrations and DDAH activity and their role
[...] Read more.
Circulating asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthesis, has been proposed as a biomarker for clinical outcome. Dimethylarginine dimethylaminohydrolase (DDAH) is the main enzyme responsible for ADMA metabolism and elimination. Adipose tissue ADMA concentrations and DDAH activity and their role in diabetes and obesity have not yet been investigated. In this study, we evaluated clinical microdialysis in combination with a sensitive analytical method (GC-MS/MS) to measure ADMA concentrations in extracellular fluid. Adipose tissue ADMA concentrations were assessed before and during an oral glucose tolerance test in lean healthy subjects and subjects with diabetes (n = 4 each), and in morbidly obese subjects before and after weight loss of 30 kg (n = 7). DDAH activity was determined in subcutaneous and visceral adipose tissue obtained during laparoscopic surgery (n = 5 paired samples). Mean interstitial ADMA concentrations did not differ between study populations (healthy 0.17 ± 0.03 µM; diabetic 0.21 ± 0.03 µM; morbidly obese 0.16 ± 0.01 and 0.17 ± 0.01 µM before and after weight loss, respectively). We did not observe any response of interstitial ADMA concentrations to the oral glucose challenge. Adipose tissue DDAH activity was negligible compared to liver tissue. Thus, adipose tissue ADMA plays a minor role in NO-dependent regulation of adipose tissue blood flow and metabolism. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Opposite Associations of Plasma Homoarginine and Ornithine with Arginine in Healthy Children and Adolescents
Int. J. Mol. Sci. 2013, 14(11), 21819-21832; doi:10.3390/ijms141121819
Received: 12 August 2013 / Revised: 20 September 2013 / Accepted: 9 October 2013 / Published: 4 November 2013
Cited by 10 | PDF Full-text (227 KB) | HTML Full-text | XML Full-text
Abstract
Homoarginine, a non-proteinogenic amino acid, is formed when lysine replaces ornithine in reactions catalyzed by hepatic urea cycle enzymes or lysine substitutes for glycine as a substrate of renal arginine:glycine amidinotransferase. Decreased circulating homoarginine and elevated ornithine, a downstream product of arginase, predict
[...] Read more.
Homoarginine, a non-proteinogenic amino acid, is formed when lysine replaces ornithine in reactions catalyzed by hepatic urea cycle enzymes or lysine substitutes for glycine as a substrate of renal arginine:glycine amidinotransferase. Decreased circulating homoarginine and elevated ornithine, a downstream product of arginase, predict adverse cardiovascular outcome. Our aim was to investigate correlates of plasma homoarginine and ornithine and their relations with carotid vascular structure in 40 healthy children and adolescents aged 3–18 years without coexistent diseases or subclinical carotid atherosclerosis. Homoarginine, ornithine, arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were measured by liquid chromatography-tandem mass spectrometry with stable isotope-labeled internal standards. Intima-media thickness (IMT) and extra-medial thickness (EMT) of common carotid arteries were estimated by B-mode ultrasound. Homoarginine correlated with arginine (r = 0.43, p = 0.005), age (r = 0.42, p = 0.007) and, weakly, with an increased arginine-to-ornithine ratio, a putative measure of lower arginase activity (r = 0.31, p = 0.048). Ornithine correlated inversely with arginine (r = −0.64, p < 0.001). IMT, EMT or their sum were unrelated to any of the biochemical parameters (p > 0.12). Thus, opposite associations of plasma homoarginine and ornithine with arginine may partially result from possible involvement of arginase, an enzyme controlling homoarginine degradation and ornithine synthesis from arginine. Age-dependency of homoarginine levels can reflect developmental changes in homoarginine metabolism. However, neither homoarginine nor ornithine appears to be associated with carotid vascular structure in healthy children and adolescents. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Associations between Endogenous Dimethylarginines and Renal Function in Healthy Children and Adolescents
Int. J. Mol. Sci. 2012, 13(11), 15464-15474; doi:10.3390/ijms131115464
Received: 9 November 2012 / Revised: 16 November 2012 / Accepted: 19 November 2012 / Published: 21 November 2012
Cited by 2 | PDF Full-text (219 KB) | HTML Full-text | XML Full-text
Abstract
The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship in healthy subjects younger than 18 years of age are rare.
[...] Read more.
The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship in healthy subjects younger than 18 years of age are rare. Therefore, our aim was to investigate relations between endogenous dimethylarginines and renal function indices in healthy children and adolescents. We studied 40 subjects aged 3–18 years free of coexistent diseases or subclinical carotid atherosclerosis. A serum creatinine-derived estimated GFR (eGFR) was calculated by the revised bedside Schwartz equation. L-arginine, ADMA and SDMA were measured by liquid chromatography-tandem mass spectrometry. Mean eGFR was 122 ± 22 (SD) mL/min per 1.73 m2. Creatinine and eGFR exhibited closer correlations with the SDMA/ADMA ratio (r = 0.64, p < 0.0001; r = −0.63, p < 0.0001, respectively) than with SDMA (r = 0.31, p = 0.05; r = −0.35, p = 0.03). Neither creatinine nor eGFR correlated with ADMA or L-arginine. Adjustment for age or height only slightly attenuated the associations between the SDMA/ADMA ratio and eGFR or creatinine. Our findings suggest the superiority of the SDMA/ADMA ratio over SDMA as a renal function index in healthy children. Thus, further studies are warranted to verify our preliminary results in a larger group of subjects below 18 years of age. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessArticle Mechanism of Cellular Oxidation Stress Induced by Asymmetric Dimethylarginine
Int. J. Mol. Sci. 2012, 13(6), 7521-7531; doi:10.3390/ijms13067521
Received: 2 May 2012 / Revised: 7 June 2012 / Accepted: 13 June 2012 / Published: 18 June 2012
Cited by 12 | PDF Full-text (256 KB) | HTML Full-text | XML Full-text
Abstract
The mechanism by which asymmetric dimethylarginine (ADMA) induces vascular oxidative stress is not well understood. In this study, we utilized human umbilical vein endothelial cells (HUVEC) to examine the roles of ADMA cellular transport and the uncoupling of endothelial nitric oxide synthase (eNOS)
[...] Read more.
The mechanism by which asymmetric dimethylarginine (ADMA) induces vascular oxidative stress is not well understood. In this study, we utilized human umbilical vein endothelial cells (HUVEC) to examine the roles of ADMA cellular transport and the uncoupling of endothelial nitric oxide synthase (eNOS) in contributing to this phenomenon. Dihydroethidium (DHE) fluorescence was used as an index of oxidative stress. Whole cells and their isolated membrane fractions exhibited measureable increased DHE fluorescence at ADMA concentrations greater than 10 µM. ADMA-induced DHE fluorescence was inhibited by co-incubation with L-lysine, tetrahydrobiopterin (BH4), or L-nitroarginine methyl ester (L-NAME). Oxidative stress induced in these cells by angiotensin II (Ang II) were unaffected by the same concentrations of L-lysine, L-NAME and BH4. ADMA-induced reduction in cellular nitrite or nitrite/nitrate production was reversed in the presence of increasing concentrations of BH4. These results suggest that ADMA-induced DHE fluorescence involves the participation of both the cationic transport system in the cellular membrane and eNOS instead of the Ang II-NADPH oxidase pathway. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)

Review

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Open AccessReview Increased Circulatory Asymmetric Dimethylarginine and Multiple Organ Failure: Bile Duct Ligation in Rat as a Model
Int. J. Mol. Sci. 2014, 15(3), 3989-4006; doi:10.3390/ijms15033989
Received: 5 December 2013 / Revised: 4 February 2014 / Accepted: 26 February 2014 / Published: 5 March 2014
Cited by 6 | PDF Full-text (343 KB) | HTML Full-text | XML Full-text
Abstract
Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher
[...] Read more.
Bile duct ligation (BDL)-treated rats exhibit cholestasis, increased systemic oxidative stress, and liver fibrosis, which ultimately lead to liver cirrhosis. Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of nitric oxide synthase that can decrease the synthesis of nitric oxide. BDL rats have higher plasma and hepatic ADMA levels, which may be due to increased hepatic protein arginine methyltransferase-1 and decreased dimethylarginine dimethylaminohydrolase expression. BDL rats also exhibit renal and brain damage characterized by increased tissue ADMA concentrations. The increased plasma ADMA levels and multiple organ damages seen here are also observed following multiple organ failures associated with critical illness. This review discusses the dysregulation of ADMA in major organs in BDL rats and the role of increased ADMA in multiple organ damages. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessReview Asymmetric Dimethyarginine as Marker and Mediator in Ischemic Stroke
Int. J. Mol. Sci. 2012, 13(12), 15983-16004; doi:10.3390/ijms131215983
Received: 28 September 2012 / Revised: 14 November 2012 / Accepted: 21 November 2012 / Published: 28 November 2012
Cited by 25 | PDF Full-text (334 KB) | HTML Full-text | XML Full-text
Abstract
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is known as mediator of endothelial cell dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia,arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. Accordingly, clinical studies
[...] Read more.
Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is known as mediator of endothelial cell dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. Accordingly, clinical studies found evidence that increased ADMA levels are associated with a higher risk of cerebrovascular events. After the acute event of ischemic stroke, levels of ADMA and its analog symmetric dimethylarginine (SDMA) are elevated through augmentation of protein methylation and oxidative stress. Furthermore, cleavage of ADMA through dimethylarginine dimethylaminohydrolases (DDAHs) is reduced. This increase of dimethylarginines might be predictive for adverse clinical outcome. However, the definite role of ADMA after acute ischemic stroke still needs to be clarified. On the one hand, ADMA might contribute to brain injury by reduction of cerebral blood flow. On the other hand, ADMA might be involved in NOS-induced oxidative stress and excitotoxic neuronal death. In the present review, we highlight the current knowledge from clinical and experimental studies on ADMA and its role for stroke risk and ischemic brain injury in the hyperacute stage after stroke. Finally, further studies are warranted to unravel the relevance of the close association of dimethylarginines with stroke. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessReview Roles of Nitric Oxide and Asymmetric Dimethylarginine in Pregnancy and Fetal Programming
Int. J. Mol. Sci. 2012, 13(11), 14606-14622; doi:10.3390/ijms131114606
Received: 12 July 2012 / Revised: 17 October 2012 / Accepted: 7 November 2012 / Published: 9 November 2012
Cited by 15 | PDF Full-text (307 KB) | HTML Full-text | XML Full-text
Abstract
Nitric oxide (NO) regulates placental blood flow and actively participates in trophoblast invasion and placental development. Asymmetric dimethylarginine (ADMA) can inhibit NO synthase, which generates NO. ADMA has been associated with uterine artery flow disturbances such as preeclampsia. Substantial experimental evidence has reliably
[...] Read more.
Nitric oxide (NO) regulates placental blood flow and actively participates in trophoblast invasion and placental development. Asymmetric dimethylarginine (ADMA) can inhibit NO synthase, which generates NO. ADMA has been associated with uterine artery flow disturbances such as preeclampsia. Substantial experimental evidence has reliably supported the hypothesis that an adverse in utero environment plays a role in postnatal physiological and pathophysiological programming. Growing evidence suggests that the placental nitrergic system is involved in epigenetic fetal programming. In this review, we discuss the roles of NO and ADMA in normal and compromised pregnancies as well as the link between placental insufficiency and epigenetic fetal programming. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessReview Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders
Int. J. Mol. Sci. 2012, 13(10), 12383-12400; doi:10.3390/ijms131012383
Received: 3 September 2012 / Revised: 19 September 2012 / Accepted: 19 September 2012 / Published: 27 September 2012
Cited by 12 | PDF Full-text (275 KB) | HTML Full-text | XML Full-text
Abstract
Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein
[...] Read more.
Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessReview Asymmetric Dimethylarginine as a Surrogate Marker of Endothelial Dysfunction and Cardiovascular Risk in Patients with Systemic Rheumatic Diseases
Int. J. Mol. Sci. 2012, 13(10), 12315-12335; doi:10.3390/ijms131012315
Received: 20 August 2012 / Revised: 15 September 2012 / Accepted: 19 September 2012 / Published: 26 September 2012
Cited by 23 | PDF Full-text (364 KB) | HTML Full-text | XML Full-text
Abstract
The last few decades have witnessed an increased life expectancy of patients suffering with systemic rheumatic diseases, mainly due to improved management, advanced therapies and preventative measures. However, autoimmune disorders are associated with significantly enhanced cardiovascular morbidity and mortality not fully explained by
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The last few decades have witnessed an increased life expectancy of patients suffering with systemic rheumatic diseases, mainly due to improved management, advanced therapies and preventative measures. However, autoimmune disorders are associated with significantly enhanced cardiovascular morbidity and mortality not fully explained by traditional cardiovascular disease (CVD) risk factors. It has been suggested that interactions between high-grade systemic inflammation and the vasculature lead to endothelial dysfunction and atherosclerosis, which may account for the excess risk for CVD events in this population. Diminished nitric oxide synthesis—due to down regulation of endothelial nitric oxide synthase—appears to play a prominent role in the imbalance between vasoactive factors, the consequent impairment of the endothelial hemostasis and the early development of atherosclerosis. Asymmetric dimethylarginine (ADMA) is one of the most potent endogenous inhibitors of the three isoforms of nitric oxide synthase and it is a newly discovered risk factor in the setting of diseases associated with endothelial dysfunction and adverse cardiovascular events. In the context of systemic inflammatory disorders there is increasing evidence that ADMA contributes to the vascular changes and to endothelial cell abnormalities, as several studies have revealed derangement of nitric oxide/ADMA pathway in different disease subsets. In this article we discuss the role of endothelial dysfunction in patients with rheumatic diseases, with a specific focus on the nitric oxide/ADMA system and we provide an overview on the literature pertaining to ADMA as a surrogate marker of subclinical vascular disease. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
Open AccessReview Asymmetric Dimethylarginine, Endothelial Dysfunction and Renal Disease
Int. J. Mol. Sci. 2012, 13(9), 11288-11311; doi:10.3390/ijms130911288
Received: 2 August 2012 / Revised: 28 August 2012 / Accepted: 3 September 2012 / Published: 10 September 2012
Cited by 30 | PDF Full-text (633 KB) | HTML Full-text | XML Full-text
Abstract
L-Arginine (Arg) is oxidized to L-citrulline and nitric oxide (NO) by the action of endothelial nitric oxide synthase (NOS). In contrast, protein-incorporated Arg residues can be methylated with subsequent proteolysis giving rise to methylarginine compounds, such as asymmetric dimethylarginine (ADMA) that competes with
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L-Arginine (Arg) is oxidized to L-citrulline and nitric oxide (NO) by the action of endothelial nitric oxide synthase (NOS). In contrast, protein-incorporated Arg residues can be methylated with subsequent proteolysis giving rise to methylarginine compounds, such as asymmetric dimethylarginine (ADMA) that competes with Arg for binding to NOS. Most ADMA is degraded by dimethylarginine dimethyaminohydrolase (DDAH), distributed widely throughout the body and regulates ADMA levels and, therefore, NO synthesis. In recent years, several studies have suggested that increased ADMA levels are a marker of atherosclerotic change, and can be used to assess cardiovascular risk, consistent with ADMA being predominantly absorbed by endothelial cells. NO is an important messenger molecule involved in numerous biological processes, and its activity is essential to understand both pathogenic and therapeutic mechanisms in kidney disease and renal transplantation. NO production is reduced in renal patients because of their elevated ADMA levels with associated reduced DDAH activity. These factors contribute to endothelial dysfunction, oxidative stress and the progression of renal damage, but there are treatments that may effectively reduce ADMA levels in patients with kidney disease. Available data on ADMA levels in controls and renal patients, both in adults and children, also are summarized in this review. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)
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Open AccessTechnical Note Determination of Homoarginine, Arginine, NMMA, ADMA, and SDMA in Biological Samples by HPLC-ESI-Mass Spectrometry
Int. J. Mol. Sci. 2013, 14(10), 20131-20138; doi:10.3390/ijms141020131
Received: 29 July 2013 / Revised: 28 August 2013 / Accepted: 18 September 2013 / Published: 9 October 2013
Cited by 5 | PDF Full-text (208 KB) | HTML Full-text | XML Full-text
Abstract
NG,NG-dimethyl-L-arginine (ADMA) and NG-methyl-L-arginine (NMMA) are endogenous inhibitors of nitric oxide synthase (NOS). In contrast, NG,N'G-dimethyl-L-arginine (SDMA) possesses only a weak inhibitory potency towards neuronal NOS and it is known
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NG,NG-dimethyl-L-arginine (ADMA) and NG-methyl-L-arginine (NMMA) are endogenous inhibitors of nitric oxide synthase (NOS). In contrast, NG,N'G-dimethyl-L-arginine (SDMA) possesses only a weak inhibitory potency towards neuronal NOS and it is known to limit nitric oxide (NO) production by competing with L-arginine for cellular uptake. The inhibition of NOS is associated with endothelial dysfunction in cardiovascular diseases as well in chronic renal failure. L-Homoarginine (HArg), a structural analog of L-arginine (Arg), is an alternative but less efficient substrate for NOS. Besides, it inhibits arginase, leading to an increased availability of L-arginine for NOS to produce NO. However, its relation with cardiovascular disease remains unclear. To date, several analytical methods for the quantitative determination of Arg, HArg, NMMA, AMDA, and SDMA in biological samples have been described. Here, we present a simple, fast, and accurate HPLC-ESI-MS/MS method which allows both the simultaneous determination and quantification of these compounds without needing derivatization, and the possibility to easily modulate the chromatographic separation between HArg and NMMA (or between SDMA and ADMA). Data on biological samples revealed the feasibility of the method, the minimal sample preparation, and the fast run time which make this method very suitable and accurate for analysis in the basic and clinical settings. Full article
(This article belongs to the Special Issue ADMA and Nitrergic System)

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