Abstract
BackgroundSerum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level.MethodsData on clinical and demographic characteristics, medication exposure, C-reactive protein, serum ADMA and SDMA (LC-MS/MS), and thiols (homocysteine, cysteine, taurine, glutamylcysteine, total glutathione, and cysteinylglycine; capillary electrophoresis) were collected from a sample of the Hunter Community Study on human ageing [n = 498, median age (IQR) = 64 (60–70) years].ResultsRegression analysis showed that: a) age (P = 0.001), gender (P = 0.03), lower estimated glomerular filtration rate (eGFR, P = 0.08), body mass index (P = 0.008), treatment with beta-blockers (P = 0.03), homocysteine (P = 0.02), and glutamylcysteine (P = 0.003) were independently associated with higher ADMA concentrations; and b) age (P = 0.001), absence of diabetes (P = 0.001), lower body mass index (P = 0.01), lower eGFR (P<0.001), cysteine (P = 0.007), and glutamylcysteine (P<0.001) were independently associated with higher SDMA concentrations. No significant associations were observed between methylated arginines and either glutathione or taurine concentrations.ConclusionsAfter adjusting for clinical, demographic, biochemical, and pharmacological confounders the combined assessment of transsulfuration pathway thiols shows that glutamylcysteine has the strongest and positive independent associations with ADMA and SDMA. Whether this reflects a direct effect of glutamylcysteine on DDAH activity (for ADMA) and/or cationic amino acid transport requires further investigations.
Highlights
The methylated forms of the amino acid L-arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine, are generated from the proteolysis of proteins containing methylated arginine residues [1,2]
Variables showing associations with either ADMA or symmetric dimethylarginine (SDMA) (P,0.2) were entered in linear stepwise regression analysis to identify factors independently associated with methylated arginines
A total of 31 variables were identified a priori to be potentially associated with the outcomes of interest: age, gender, body mass index, smoking, alcohol consumption, history of hypertension, hypercholesterolaemia, rheumatoid arthritis, myocardial infarction, stroke, diabetes, fasting glucose, total cholesterol, HDL and LDL cholesterol, triglycerides, Estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), homocysteine, cysteine, taurine, glutamylcysteine, glutathione, cysteinylglycine, and use of antiplatelet drugs, beta-blockers, angiotensin converting enzyme inhibitors, statins, diuretics, calcium channel blockers, and antidiabetic drugs
Summary
The methylated forms of the amino acid L-arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine, are generated from the proteolysis of proteins containing methylated arginine residues [1,2]. Both ADMA and, to a lesser extent, SDMA play an important role in cardiovascular homeostasis. ADMA is a potent endogenous inhibitor of endothelium nitric oxide synthase [1,2]. Serum homocysteine, when studied singly, has been reported to be positively associated both with the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine [ADMA, via inhibition of dimethylarginine dimethylaminohydrolase (DDAH) activity] and with symmetric dimethylarginine (SDMA). We investigated combined associations between transsulfuration pathway thiols, including homocysteine, and serum ADMA and SDMA concentrations at population level
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