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. CONCLUSIONS: 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.
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. CONCLUSIONS: 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.
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