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

Xinli Hu, Dorothee Atzler, Xin Xu, Ping Zhang, Haipeng Guo, Zhongbing Lu, John Fassett, Edzard Schwedhelm, Rainer H. Böger, Robert J Bache, Yingjie Chen

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)1540-1546
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number7
DOIs
StatePublished - Jul 1 2011

Keywords

  • asymmetric dimethylarginine, dimethylarginine dimethylaminohydrolase 1
  • knockout mice
  • nitric oxide

Fingerprint Dive into the research topics of 'Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine'. Together they form a unique fingerprint.

  • Cite this