Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia.
BACKGROUND
Hyperhomocysteinemia is a cardiovascular risk factor that is associated with elevation of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA).


OBJECTIVE
Using mice transgenic for overexpression of the ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1), we tested the hypothesis that overexpression of DDAH1 protects from adverse structural and functional changes in cerebral arterioles in hyperhomocysteinemia.


RESULTS
Hyperhomocysteinemia was induced in DDAH1 transgenic (DDAH1 Tg) mice and wild-type littermates using a high methionine/low folate (HM/LF) diet. Plasma total homocysteine was elevated approximately 3-fold in both wild-type and DDAH1 Tg mice fed the HM/LF diet compared with the control diet (P<0.001). Plasma ADMA was approximately 40% lower in DDAH1 Tg mice compared with wild-type mice (P<0.001) irrespective of diet. Compared with the control diet, the HM/LF diet diminished endothelium-dependent dilation to 10 micromol/L acetylcholine in cerebral arterioles of both wild-type (12 + or - 2 versus 29 + or - 3%; P<0.001) and DDAH1 Tg (14 + or - 3 versus 28 + or - 2%; P<0.001) mice. Responses to 10 micromol/L papaverine, a direct smooth muscle dilator, were impaired with the HM/LF diet in wild-type mice (30 + or - 3 versus 45 + or - 5%; P<0.05) but not DDAH1 Tg mice (45 + or - 7 versus 48 + or - 6%). DDAH1 Tg mice also were protected from hypertrophy of cerebral arterioles (P<0.05) but not from accelerated carotid artery thrombosis induced by the HM/LF diet.


CONCLUSIONS
Overexpression of DDAH1 protects from hyperhomocysteinemia-induced alterations in cerebral arteriolar structure and vascular muscle function.
Rodionov
Roman N
RN
Department of Internal Medicine, C32 GH, The University of Iowa, Iowa City, IA 52242, USA.
Dayoub
Hayan
H
Lynch
Cynthia M
CM
Wilson
Katina M
KM
Stevens
Jeff W
JW
Murry
Daryl J
DJ
Kimoto
Masumi
M
Arning
Erland
E
Bottiglieri
Teodoro
T
Cooke
John P
JP
Baumbach
Gary L
GL
Faraci
Frank M
FM
Lentz
Steven R
SR
D000109:Acetylcholine / Q000494:pharmacology; D000581:Amidohydrolases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D001160:Arterioles / Q000473:pathology*; D002341:Carotid Artery Thrombosis / Q000209:etiology; D002539:Cerebral Arterial Diseases / Q000209:etiology / Q000517:prevention & control*; D004032:Diet / Q000009:adverse effects; D005494:Folic Acid Deficiency / Q000150:complications; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D006984:Hypertrophy; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010208:Papaverine / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; C018524:N,N-dimethylarginine; D001120:Arginine; D008715:Methionine; D010208:Papaverine; D000581:Amidohydrolases; C059999:dimethylargininase; D000109:Acetylcholine