Dimethylarginine Dimethylaminohydrolase-1 Is the Critical Enzyme for Degrading the Cardiovascular Risk Factor Asymmetrical Dimethylarginine (original) (raw)
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AJP: Heart and Circulatory Physiology, 2007
Asymmetric ( NG, NG)-dimethylarginine (ADMA) inhibits nitric oxide (NO) synthases (NOS). ADMA is a risk factor for endothelial dysfunction, cardiovascular mortality, and progression of chronic kidney disease. Two isoforms of dimethylarginine dimethylaminohydrolase (DDAH) metabolize ADMA. DDAH-1 is the predominant isoform in the proximal tubules of the kidney and in the liver. These organs extract ADMA from the circulation. DDAH-2 is the predominant isoform in the vasculature, where it is found in endothelial cells adjacent to the cell membrane and in intracellular vesicles and in vascular smooth muscle cells among the myofibrils and the nuclear envelope. In vivo gene silencing of DDAH-1 in the rat and DDAH +/− mice both have increased circulating ADMA, whereas gene silencing of DDAH-2 reduces vascular NO generation and endothelium-derived relaxation factor responses. DDAH-2 also is expressed in the kidney in the macula densa and distal nephron. Angiotensin type 1 receptor activation...
Circulation, 1999
Background-Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Plasma levels of ADMA are elevated in individuals with hypercholesterolemia or atherosclerosis. We postulated that reduced degradation of ADMA may play a role in the accumulation of ADMA in these individuals. Accordingly, we studied the effects of oxidized LDL (oxLDL) or tumor necrosis factor-␣ (TNF-␣) on the accumulation of ADMA by transformed human umbilical vein endothelial cells (ECV304) and on the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which degrades ADMA. Methods and Results-ECV304 were incubated with or without native LDL (100 g/mL), oxLDL (100 g/mL), or TNF-␣ (250 U/mL) for 48 hours. The concentration of ADMA in the conditioned medium was determined by high-performance liquid chromatography. Western blotting was performed to evaluate DDAH expression. We assayed DDAH activity by determining L-citrulline formation from ADMA. The addition of oxLDL or TNF-␣ to ECV304 significantly increased the level of ADMA in the conditioned medium. The effect of oxLDL or TNF-␣ was not due to a change in DDAH expression but rather to the reduction of DDAH activity. To determine whether dysregulation of DDAH also occurred in vivo, New Zealand White rabbits were fed normal chow or a high-cholesterol diet. Hypercholesterolemia significantly reduced aortic, renal, and hepatic DDAH activity. Conclusions-These results suggest that the endothelial vasodilator dysfunction observed in hypercholesterolemia may be due to reduced degradation of ADMA, the endogenous inhibitor of NOS. (Circulation. 1999;99:3092-3095.)
The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor
Cardiovascular Research, 2003
There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions (i.e., 3-15 mmol / l); ADMA also causes local vasoconstriction when it is infused intraarterially. The biochemical and physiological pathways related to ADMA are now well understood: dimethylarginines are the result of the degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, SDMA, are eliminated from the body by renal excretion, whereas only ADMA, but not SDMA, is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and / or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With our increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic intervention. Among other treatments, the administration of L-arginine has been shown to improve endotheliumdependent vascular function in subjects with high ADMA levels.
Biological Functional Relevance of Asymmetric Dimethylarginine (ADMA) in Cardiovascular Disease
International Journal of Molecular Sciences, 2013
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.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2011
Objective— Dimethylarginine dimethylaminohydrolase 1 (DDAH1) modulates NO production by degrading the endogenous nitric oxide (NO) synthase (NOS) inhibitors asymmetrical dimethylarginine (ADMA) and L-NG-monomethyl arginine (L-NMMA). This study examined whether, in addition to degrading ADMA, DDAH1 exerts ADMA-independent effects that influence endothelial function. Methods and Results— Using selective gene silencing of DDAH1 with small interfering RNA and overexpression of DDAH1 in human umbilical vein endothelial cells, we found that DDAH1 acts to promote endothelial cell proliferation, migration, and tube formation by Akt phosphorylation, as well as through the traditional role of degrading ADMA. Incubation of human umbilical vein endothelial cells with the NOS inhibitors l -NG-nitro-arginine methyl ester (L-NAME) or ADMA, the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3–2)quinoxalin-1-one, or the cGMP analog 8-(4-Chlorophenylthio)-cGMP had no effect on phosphoryla...
Effect of asymmetric dimethylarginine (ADMA) on heart failure development
Nitric Oxide, 2016
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases that limits nitric oxide bioavailability and can increase production of NOS derived reactive oxidative species. Increased plasma ADMA is a one of the strongest predictors of mortality in patients who have had a myocardial infarction or suffer from chronic left heart failure, and is also an independent risk factor for several other conditions that contribute to heart failure development, including hypertension, coronary artery disease/atherosclerosis, diabetes, and renal dysfunction. The enzyme responsible for ADMA degradation is dimethylarginine dimethylaminohydrolase-1 (DDAH1). DDAH1 plays an important role in maintaining nitric oxide bioavailability and preserving cardiovascular function in the failing heart. Here, we examine mechanisms of abnormal NO production in heart failure, with particular focus on the role of ADMA and DDAH1.