title: Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine.
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).
  
  
  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.
authors.affiliation: Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Dorothee
authors.initials: D
authors.lastname: Atzler
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Haipeng
authors.initials: H
authors.lastname: Guo
authors.forename: Zhongbing
authors.initials: Z
authors.lastname: Lu
authors.forename: John
authors.initials: J
authors.lastname: Fassett
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D012307:Risk Factors; D013379:Substrate Specificity; D013997:Time Factors; D014162:Transfection; D019323:omega-N-Methylarginine / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase; D019331:NG-Nitroarginine Methyl Ester