Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes

Krzyżanowska, Katarzyna; Mittermayer, Friedrich; Krugluger, Walter; Schnack, Ch.; Hofer, Martin; Wolzt, Michael; Schernthaner, Guntram

doi:10.1016/j.atherosclerosis.2005.12.007

Cited by 62 publications

(38 citation statements)

References 28 publications

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“…The concentration of SDMA was calculated by graphing the ratio of peak area (SDMA) to area of the internal standard versus concentration. The concentration of ADMA showed significant difference between healthy controls and T2DM (pϽ0.05), The level of ADMA was much higher in T2DM patients compared to healthy controls, which indicated that ADMA had associativity with T2DM, and this was coincidence with other's research, [26][27][28][29][30] shown in Table 7. The concentration of SDMA and L-Arg showed no significant deviation among the three groups, which indicated that they had not associativity with T2DM (pϾ0.05).…”

Section: Resultssupporting

confidence: 68%

Quantitation of L-Arginine and Asymmetric Dimethylarginine in Human Plasma by LC-Selective Ion Mode-MS for Type 2 Diabetes Mellitus Study

Zhang

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Regular ArticleAsymmetric dimethylarginine (ADMA) and its inactive stereoisomer symmetric dimethylarginine (SDMA) are hydrolysation products of proteins with methylated arginine residues, 1) which are synthesized by endothelial cells, circulated in human plasma and excreted in the urine.2) Nitric oxide (NO) is known as the star molecule due to its pleiotropic effects on physiology, for example, relaxing vessels, decreasing the blood pressure 3) and adjusting insulin. 4)L-Argnine (L-Arg) serves as a substrate for the enzyme NO synthesis (NOS), whereas ADMA is an endogenous NOS inhibitor 2) and a competitive inhibitor of the cellular L-Arg uptake.1) It reduces nitric oxide production, which causes the dysfunction of endothelium and cardiovascular disease. 5) In human, SDMA is produced in equivalent quantities, although it has no direct inhibitory effect on NO synthesis. 6) Clinic cases have proved that the level of ADMA is related with cardiovascular disease and ADMA may be a new biomarker in cardiovascular diseases. 7) In addition, Rask-Madsen et al. 4)found ADMA was associated with insulin resistance and diabetes to some extent. There is a growing literature implicating ADMA as a key player in endothelial dysfunction. Therefore, accurate and reliable quantification of these substances in plasma is essential for clinical significance. Nowadays, many methods for determination of L-Arg and ADMA have been reported. [8][9][10][11][12][13] Among these methods, high-performance liquid chromatography (HPLC) might be the most widely used one. Furthermore, the o-phthaldialdehyde (OPA) 8) and 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) 9) and the other derivatization reagents pre-column fluorescence derivatization technique 10,11) are employed to increase the detectability in all the reported HPLC methods. These methods are time-consuming and lack of selectivity. 14)Although the analytical time of the capillary electrophoresis is short, the sample preparation is tedious.12) Given these shortcomings of existing techniques, our purpose is to develop a simple, sensitive and fast LC/MS method for determination of ADMA in human plasma and to estimate the relationship between ADMA and type 2 diabetes mellitus (T2DM). ExperimentalReference Compounds and Chemicals L-Arginine (purity Ͼ99.0%), ADMA (purity Ͼ99.0%), SDMA (purity Ͼ99.0%) and L-homoarginine (purity Ͼ99.0%) were purchased from Sigma (St. Louis, MO, U.S.A.). HPLC grade acetonitrile was purchased from Laboratories Ltd. (Caledon, Canada) and methanol was obtained from Hanbon Sci. and Tec. of Jiangsu (China). All used water was Milli-Q grade.Equipment The HPLC system consisted of a Shimadzu LC-10Advp pump, an SCL-10Advp system controller, a CTO-10Avp column oven, an FCV-10Advp low-pressure gradient unit, a DGU-14A degasser (Shimadzu, Kyoto, Japan). The mass spectrometer was an LC/MS-2010 single quadrupole equipped with electrospray ionization interface (Shimadzu, Kyoto, Japan). The data was collected and processed using LC/MS Solution software (version 2.02).Chromatograph...

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Section: Resultssupporting

confidence: 68%

Quantitation of L-Arginine and Asymmetric Dimethylarginine in Human Plasma by LC-Selective Ion Mode-MS for Type 2 Diabetes Mellitus Study

Zhang

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…12 In a model of subarachnoid hemorrhage, elevated basal levels of ADMA in the cerebrospinal fluid were associated with cerebral vasospasm. 17 In addition to effects under normal conditions, several clinical studies have shown a strong association between elevated levels of ADMA and disease states such as atherosclerosis, 13,26 cerebral small-vessel disease, 14 transient ischemic attacks and stroke, 15,16 cerebral vasospasm, 27 and Alzheimer's disease. 18 In some reports, the association is so strong that the use of ADMA levels as a predictor of cardiac or cerebrovascular events has been suggested.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Dimethylarginine Dimethylaminohydrolase Inhibits Asymmetric Dimethylarginine–Induced Endothelial Dysfunction in the Cerebral Circulation

Dayoub

Rodionov

Lynch

et al. 2008

Stroke

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Background and Purpose-Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). An elevation of plasma ADMA levels is associated with cardiovascular disease. ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1-Tg) mice inhibits the vascular effects of ADMA. Methods-Using nontransgenic (non-Tg) and DDAH-1-Tg mice, we compared responses of the carotid artery and aorta (in vitro) and of the cerebral arterioles (in vivo) in the absence or presence of ADMA. DDAH-1 expression and plasma levels of ADMA were also measured. Results-Western blotting indicated that vascular expression of DDAH-1 was increased markedly in DDAH-1-Tg mice.Plasma levels of ADMA were reduced by Ϸ50% in DDAH-1-Tg mice compared with non-Tg mice (0.19Ϯ0.02 vs 0.37Ϯ0.04 mol/L, PϽ0.05). Contraction of the aorta to nitro-L-arginine methyl ester (an inhibitor of NOS), an index of basal production of NO, was increased in DDAH-1-Tg mice compared with controls (50Ϯ4% vs 34Ϯ4%, PϽ0.05).Relaxation of the carotid artery to acetylcholine (an endothelium-dependent agonist) was enhanced in DDAH-1-Tg animals compared with control mice (relaxation of 74Ϯ6% vs 59Ϯ5%, respectively, in response to 10 mol/L acetylcholine, PϽ0.05). ADMA (100 mol/L) impaired the vascular response to acetylcholine in both non-Tg and DDAH-1-Tg mice, but the relative difference between the 2 strains remained. Responses to the endotheliumindependent NO donor nitroprusside were similar in all groups. In vivo, ADMA (10 mol/L) reduced responses of the cerebral arterioles to acetylcholine by Ϸ70% in non-Tg mice (PϽ0.05), and this inhibitory effect was largely absent in DDAH-1-Tg mice. Conclusions-These findings provide the first evidence that overexpression of DDAH-1 increases basal levels of vascular NO and protects against ADMA-induced endothelial dysfunction in the cerebral circulation. Key Words: carotid arteries Ⅲ cerebral arterioles Ⅲ endothelium Ⅲ genetically altered mice Ⅲ nitric oxide N itric oxide (NO) production by NO synthases (NOSs) regulates cerebrovascular tone and brain perfusion as well as inhibits abnormal vascular growth. 1,2 Methylated arginine analogues such as N G -monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA) are produced endogenously during cellular turnover of methylated proteins and competitively inhibit NOS. [3][4][5] The major pathway for metabolism of ADMA is through hydrolysis by dimethylarginine dimethylaminohydrolases (DDAH). 4,6,7 Two DDAH genes, DDAH-1 and DDAH-2, have been described. 8,9 Exogenous ADMA produces vasoconstriction and inhibition of endothelial function in cerebral arteries from several species, including humans. 10,11 In healthy human subjects, ADMA decreases brain perfusion and increases arterial stiffness. 12 Increased plasma levels of ADMA are present in patients with atherosclerosis, 13 cerebral small-vessel disease, 14 transient ischemic attacks and stroke, 15,1...

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“…It was found that the most fundamental determinant of ADMA is total homocysteine (tHcy). Moreover, Krzyzanowska et al [84] showed that ADMA is related to clinical CV atherosclerotic disease diagnosis in T2DM, and also concluded that ADMA is associated with total tHcy, U-Alb, Cr, and GFR and that tHcy correlates with…”

Section: Adma and Dm Complicationsmentioning

confidence: 99%

“…Konya H et al . ADMA, a biomarker of cardiovascular complications in DM age, ADMA, Cr, GFR, and LDL [84] . Research has also shown that increased tHcy concentration in T2DM is associated with increased CV complications [85,86] .…”

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confidence: 99%

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus

Konya

Miuchi

Satani

et al. 2015

WJEM

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Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized β = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects. Core tip: Asymmetric dimethylarginine (ADMA) is an emerging independent biomarker for prospective cardiovascular (CV) complications. In our study, the results show that the cases with a high level of ADMA could have diabetes mellitus CV (DMCV) complications in the future within five years. Furthermore, not only ADMA but also urinary albumin was associated with DMCV complications in the multiple regression analyses. The clinical acceptation of this parameter will rely on the availability of therapies to immediately reduce ADMA such as incretin-based drugs, which could support the part of ADMA as an etiologic risk factor.

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Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes

Cited by 62 publications

References 28 publications

Quantitation of L-Arginine and Asymmetric Dimethylarginine in Human Plasma by LC-Selective Ion Mode-MS for Type 2 Diabetes Mellitus Study

Quantitation of L-Arginine and Asymmetric Dimethylarginine in Human Plasma by LC-Selective Ion Mode-MS for Type 2 Diabetes Mellitus Study

Overexpression of Dimethylarginine Dimethylaminohydrolase Inhibits Asymmetric Dimethylarginine–Induced Endothelial Dysfunction in the Cerebral Circulation

Asymmetric dimethylarginine, a biomarker of cardiovascular complications in diabetes mellitus

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