Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence.
BACKGROUND
NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis.


RESULTS
We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production.


CONCLUSIONS
DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.
Dayoub
Hayan
H
Program in Vascular Medicine and Biology, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, Calif 94305-5246, USA.
Achan
Vinod
V
Adimoolam
Shanthi
S
Jacobi
Johannes
J
Stuehlinger
Marcus C
MC
Wang
Bing-yin
BY
Tsao
Philip S
PS
Kimoto
M
M
Vallance
Patrick
P
Patterson
Andrew J
AJ
Cooke
John P
JP
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D002478:Cells, Cultured; D004727:Endothelium / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D014162:Transfection
D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase