Elevated dimethylarginine dimethylaminohydrolase (DDAH) activity in rheumatoid arthritis and spondyloarthritis

Chobanyan-Jürgens, Kristine; Pham, Vu Vi; Stichtenoth, Dirk O.; Tsikas, Dimitrios

doi:10.1016/j.niox.2011.08.003

Cited by 9 publications

(6 citation statements)

References 14 publications

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“…This is close to the DMA excretion rate of 60 ± 12 mmol DMA/mol creatinine measured in another cohort of 28 patients with rheumatic diseases including RA (Chobanyan-Jürgens et al 2011). Similar excretion rates of DMA (53 ± 2.65 mmol DMA/mol creatinine, n = 49) were also observed in patients suffering from CAD (Tsikas et al 2007).…”

Section: Discussionsupporting

confidence: 86%

Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease

et al. 2015

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Elevated circulating concentrations of total L-homocysteine (thCys) and free asymmetric dimethylarginine (ADMA) are long-established cardiovascular risk factors. Low circulating L-homoarginine (hArg) concentrations were recently found to be associated with increased cardiovascular morbidity and mortality. The biochemical pathways of these amino acids overlap and share the same cofactor S-adenosylmethionine (SAM). In the present study, we investigated potential associations between hArg, L-arginine (Arg), ADMA and thCys in plasma of patients suffering from rheumatoid arthritis (RA), coronary artery disease (CAD) or peripheral artery occlusive disease (PAOD). In RA, we did not find any correlation between ADMA or hArg and thCys at baseline (n = 100) and after (n = 83) combined add-on supplementation of omega-3 fatty acids, vitamin E, vitamin A, copper, and selenium, or placebo (soy oil). ADMA correlated with Arg at baseline (r = 0.446, P < 0.001) and after treatment (r = 0.246, P = 0.03). hArg did not correlate with ADMA, but correlated with Arg before (r = 0.240, P = 0.02) and after treatment (r = 0.233, P = 0.03). These results suggest that hArg, ADMA and Arg are biochemically familiar with each other, but unrelated to hCys in RA. In PAOD and CAD, ADMA and thCys did not correlate.

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Section: Discussionsupporting

confidence: 86%

Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease

et al. 2015

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“…In patients with rheumatic diseases, considerable differences were found for the creatinine-corrected excretion rates of DMA and ADMA and their molar ratio, both with respect to healthy subjects and within the individual variants of rheumatoid arthritis (RA), i.e., undifferentiated RA, spondyloarthritis and vasculitis ( Table 1 ) [ 46 ]. The newly calculated relative DDAH activity in the patients of this study did not reveal any correlation with the urinary biomarkers of nitrosative and oxidative stress, 3-nitrotyrosine ( r = 0.19, p = 0.32) and 8-iso-prostaglandin F 2α (8-iso-PGF 2α ) ( r = −0.07, p = 0.73), respectively.…”

Section: Urinary Dma and Adma In Children Adolescents And Adults mentioning

confidence: 99%

“…Elevated creatinine-corrected DMA excretion rates were found in rheumatic diseases, notably in rheumatoid arthritis and spondyloarthritis [ 46 ] ( Table 1 ). In patients with rheumatoid arthritis ( n = 27), elevated creatinine-corrected excretion rates of DMA were found compared to healthy subjects ( n = 39): 50.7 (45.0–65.3) vs 23.0 (18–28.8) µmol/mmol ( p < 0.0001) [ 61 ].…”

Section: Statins Metformin L-arginine Catecholamines and The Prmentioning

confidence: 99%

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Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond

Tsikas

2020

JCM

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Asymmetric protein-arginine dimethylation is a major post-translational modification (PTM) catalyzed by protein-arginine methyltransferase (PRMT). Regular proteolysis releases asymmetric dimethylarginine (ADMA). Of the daily produced ADMA, about 10% are excreted unchanged in the urine. The remaining 90% are hydrolyzed by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline and dimethylamine (DMA), which is readily excreted in the urine. The PRMT/DDAH pathway is almost the exclusive origin of urinary ADMA and the major source of urinary DMA. Dietary fish and seafood represent additional abundant sources of urinary DMA. The present article provides an overview of urinary ADMA and DMA reported thus far in epidemiological, clinical and pharmacological studies, in connection with the L-arginine/nitric oxide (NO) pathway and beyond, in neonates, children and adolescents, young and elderly subjects, males and females. Discussed diseases mainly include those relating to the renal and cardiovascular systems such as peripheral arterial occlusive disease, coronary artery disease, chronic kidney disease, rheumatoid arthritis, Becker muscular disease, Duchenne muscular disease (DMD), attention deficit hyperactivity disorder (ADHD), and type I diabetes. Under standardized conditions involving the abstinence of DMA-rich fresh and canned fish and seafood, urinary DMA and ADMA are useful as measures of whole-body asymmetric arginine-dimethylation in health and disease. The creatinine-corrected excretion rates of DMA range from 10 to 80 µmol/mmol in adults and up to 400 µmol/mmol in children and adolescents. The creatinine-corrected excretion rates of ADMA are on average 10 times lower. In general, diseases are associated with higher urinary DMA and ADMA excretion rates, and pharmacological treatment, such as with steroids and creatine (in DMD), decreases their excretion rates, which may be accompanied by a decreased urinary excretion of nitrate, the major metabolite of NO. In healthy subjects and in rheumatoid arthritis patients, the urinary excretion rate of DMA correlates positively with the excretion rate of dihydroxyphenylglycol (DHPG), the major urinary catecholamines metabolite, suggesting a potential interplay in the PRMT/DDAH/NO pathway.

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“…For example, overproduction of NO is associated with vascular collapse in sepsis and is implicated in migraine headache, some types of cancer, and defined autoimmune diseases such as rheumatoid arthritis and spondyloarthritis. 10,11 In these cases, it seems likely that a DDAH antagonist, by elevating ADMA levels and suppressing NO synthesis, might have therapeutic value. Moreover, a recent study has shown that in an animal model of idiopathic pulmonary fibrosis (IPF), DDAH and iNOS activities are increased.…”

Section: Introductionmentioning

confidence: 99%

Development of a Dimethylarginine Dimethylaminohydrolase (DDAH) Assay for High-Throughput Chemical Screening

et al. 2012

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Nitric oxide (NO) is a potent signaling molecule that needs to be tightly regulated to maintain metabolic and cardiovascular homeostasis. The nitric oxide synthase (NOS)/Dimethylarginine dimethylaminohydrolase (DDAH)/Asymmetric Dimethylarginine (ADMA) pathway is central to this regulation. Specifically, the small molecule ADMA competitively inhibits NOS, thus lowering NO levels. The majority of ADMA is physiologically metabolized by DDAH, thus maintaining NO levels at physiological concentration. However, under pathophysiological conditions, DDAH activity is impaired, in part as a result of its sensitivity to oxidative stress. Therefore, the application of high throughput chemical screening for the discovery of small molecules that could restore or enhance DDAH activity might have significant potential in treating metabolic and vascular diseases characterized by reduced NO levels, including atherosclerosis, hypertension, and insulin resistance. By contrast, excessive generation of NO (primarily driven by iNOS) could play a role in idiopathic pulmonary fibrosis (IPF), sepsis, migraine headaches, and some types of cancer. In these conditions, small molecules that inhibit DDAH activity might be therapeutically useful. Here, we describe optimization and validation of a highly reproducible and robust assay successfully used in a high throughput screen for DDAH modulators.

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Elevated dimethylarginine dimethylaminohydrolase (DDAH) activity in rheumatoid arthritis and spondyloarthritis

Cited by 9 publications

References 14 publications

Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease

Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease

Urinary Dimethylamine (DMA) and Its Precursor Asymmetric Dimethylarginine (ADMA) in Clinical Medicine, in the Context of Nitric Oxide (NO) and Beyond

Development of a Dimethylarginine Dimethylaminohydrolase (DDAH) Assay for High-Throughput Chemical Screening

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