Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine

Objective-: The objective of this study was to identify the role of dimethylarginine dimethylaminohydrolase-1 (DDAH1) in degrading the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and N ^g-monomethyl-L-arginine (L-NMMA). Methods and Results-: We generated a global-DDAH1 gene-deficient (DDAH1^-/-) mouse strain to examine the role of DDAH1 in ADMA and L-NMMA degradation and the physiological consequences of loss of DDAH1. Plasma and tissue ADMA and L-NMMA levels in DDAH1 ^-/- mice were several folds higher than in wild-type mice, but growth and development of these DDAH1^-/- mice were similar to those of their wild-type littermates. Although the expression of DDAH2 was unaffected, DDAH activity was undetectable in all tissues tested. These findings indicate that DDAH1 is the critical enzyme for ADMA and L-NMMA degradation. Blood pressure was ≈20 mm Hg higher in the DDAH1^-/- mice than in wild-type mice, but no other cardiovascular phenotype was found under unstressed conditions. Crossing DDAH1^+/- male with DDAH1^+/- female mice yielded DDAH1^+/+, DDAH1^+/-, and DDAH1^-/- mice at the anticipated ratio of 1:2:1, indicating that DDAH1 is not required for embryonic development in this strain. Conclusion-: Our findings indicate that DDAH1 is required for metabolizing ADMA and L-NMMA in vivo, whereas DDAH2 had no detectable role for degrading ADMA and L-NMMA.