Global Dimethylarginine Dimethylaminohydrolase-1 (DDAH1) Gene–Deficient Mice Reveal That DDAH1 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 Ng-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 severalfold 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 ≈F20 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.
- Received August 27, 2010.
- Accepted March 28, 2011.
- © 2011 American Heart Association, Inc.