The Clinical Significance of Asymmetric Dimethylarginine

Abstract

▪ Abstract In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.

Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation

“…4 The predictive power of circulating ADMA levels was later also confirmed in other high-risk patient groups (reviewed in ref. 5).…”

Tight glycemic control does not affect asymmetric-dimethylarginine in septic patients

“…During the last few years, the relation between ADMA plasma levels and adverse effects has been frequently described [3,4,6,9,[11][12][13][14][15][16][17][18][19][20]. Elevation of ADMA, like other methylated aminoacids [26], quite likely results from increased protein breakdown, possibly coupled with impairment of the degrading enzyme in liver, kidney or endothelium [8], and/or renal failure.…”

“…Data are expressed as mean ± SD. The dotted line represents the upper limit of blood glucose level for the treatment group, shaded area represent the normal range (up to the 95th percentile) for asymmetric-dimethylarginine nitric oxide fine tuning of the microcirculation involving the endothelium, platelets and white blood cells [5][6][7]9] could open new therapeutic perspectives. Attempts to lower the plasma ADMA concentration have not been encouraging [17]; however, in surgical intensive care patients, Siroen et al [15] have suggested that ADMA levels could be modulated by insulin-mediated normoglycemia and this partly explained clinical beneficial effects, reduced morbidity, and mortality associated with insulin treatment.…”

“…The assumptions of the normoglycemia/insulin hypothesis in inflammatory conditions are as follows [9]: a catabolic status results in cellular ADMA spillover and high plasma levels, while hyperglycemia increases expression of the cationic amino acid transport system y+ [9,27,28] and inhibits the activity of dimethylargininehydrolase [29]. In this scenario, insulin reduces protein catabolism [26], affects the cationic amino acid y+ transport system and may thereby increase the uptake of ADMA in organs able to eliminate it [27,28,30,31].…”

“…Oxidative stress and cytokines enhance the activity of protein arginine methyltransferase, increase methylarginine release due to protein catabolism and variably influence [8,9] dimethylarginine-dimethylaminohydrolase activity in liver, kidney and pancreas, further contributing to ADMA plasma levels [8]. In the presence of high ADMA levels active dimeric isoforms of nitric oxide synthase may become uncoupled, with the generation of superoxide anion.…”