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.
|Original language||English (US)|
|Number of pages||7|
|Journal||Arteriosclerosis, thrombosis, and vascular biology|
|State||Published - Jul 2011|
- asymmetric dimethylarginine, dimethylarginine dimethylaminohydrolase 1
- knockout mice
- nitric oxide