Dimethylarginine DDAH

ADMA is degraded by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine [70,83]. Two isoforms of this enzyme have been characterized and cloned to date. DDAH I predominates in tissues that express neuronal NOS and DDAH II predominates in tissues expressing endothelial NOS [70,84]. Activity of DDAH has been shown to be decreased by oxidized low density lipoprotein (LDL) or tumor necrosis factor-a (TNF-a) in vitro yielding increased levels of ADMA. Plasma levels of ADMA were found elevated in hyperhomo-cysteinemia, hypercholesterolemia and in hypertensive patients on a high salt diet [70,72,73]. 

Figure 9 Endogenously produced, asymmetrically N -methylated arginines (12,13) inhibit NO synthase, but 14 does not. Hydrolysis of asymmetrically methylated arginine residues by dimethylarginine dimethylaminohydrolase (DDAH) can relieve this inhibition and promote NO biosynthesis.

DDAH itself may also have potential as a therapeutic protein in disease states marked by excess N dimethyl-L-arginine. For example, overexpression of DDAH has beneficial effects in transgenic mouse models of graft coronary artery disease and can enhance sensitivity to insulin. DDAH may also have beneficial effects in treating chronic kidney disease, as overexpressed DDAH appears to slow progression of renal dysfunction in rat models. " Elevated asymmetric dimethylarginine (ADMA) levels have also been identified in the development of chronic lung diseases, specifically pulmonary fibrosis. However, the causal relationship between ADMA and these conditions has yet to be explored in detail. ... 

B Reaction associated with the accumulation of S-adenosylhomocysteine (SAH) due to persistent slowing of the hydrolysis of SAH C Reactions due to the inhibition of dimethylarginine dimethylamino-hydrolase (DDAH)... 

Hyperhomocysteinemia, in coronary arteries increased TNF-a expression, which enhanced oxidative stress ultimately impairing flow-induced dilation that can be reversed by superoxide dismutase (SOD) (147). Also, in EC Hey inhibits dimethylarginine dimethylamino-hydrolase (DDAH) enzyme activity by direct interaction (enzyme that degrades asymetric dimethylarginine [ADMA]), causing ADMA to accumulate and inhibit NO synthesis, which might explain how Hey impairs NO dependent vasodilation (148). 

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