Abstract 17093: Global DDAH1 Gene--Deficient Mice Reveal that DDAH1 Is the Only Physiological Relevant Enzyme in Degrading Cardiovascular Risk Factor ADMA
Background: Asymmetric dimethylarginine (ADMA) and Ng-monomethyl-L-arginine (L-NMMA) compete with arginine to limit nitric oxide production. Accumulation of plasma ADMA and L-NMMA represents an independent risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) degrades ADMA and L-NMMA. Patients with abnormal DDAH1 function were associated with cardiovascular diseases such as coronary artery disease and stroke etc. However, physiological relevance of DDAH1 vs. DDAH2 in degrading ADMA and L-NMMA is not clear. This study examined the essential role of DDAH1 in ADMA and L-NMMA degradation, and the physiological consequences that result from loss of total DDAH activity.
Methods and Results: We generated a global-DDAH1 gene deficient (DDAH1−/−) mouse strain. Growth and development of these DDAH1−/− mice was similar to their wild type littermates. DDAH1−/− mice had normal DDAH2 expression, but plasma and tissue ADMA and L-NMMA levels were 2 to 8 fold higher than in wild type mice. Most interestingly, we have demonstrated that DDAH1−/− totally abolished tissue DDAH activity or the degradation of ADMA and L-NMMA in all tissues tested without affecting the expression of DDAH2 protein, indicating that DDAH1 is the only physiologically relevant enzyme in degrading ADMA in vivo. DDAH1−/− mice had increased blood pressure ∼20 mmHg, but had no other noticeable cardiovascular phenotypes under unstressed conditions.
Conclusions: DDAH1 is essential for tissue ADMA and L-NMMA degradation, but is not required for embryonic development. Preserved levels of DDAH2 in DDAH1−/− mice were not associated with detectable DDAH activity, indicating that DDAH2 does not degrade ADMA or L-NMMA in vivo.
- © 2010 by American Heart Association, Inc.