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Circulation Research
Year: 2010  |  Volume: 106  |  Issue: 3  |  Page No.: 551 - 558

Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia

R. N Rodionov, H Dayoub, C. M Lynch, K. M Wilson, J. W Stevens, D. J Murry, M Kimoto, E Arning, T Bottiglieri, J. P Cooke, G. L Baumbach, F. M Faraci and S. R. Lentz    

Abstract:

Rationale: 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.

Methods and 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 µmol/L acetylcholine in cerebral arterioles of both wild-type (12±2 versus 29±3%; P<0.001) and DDAH1 Tg (14±3 versus 28±2%; P<0.001) mice. Responses to 10 µmol/L papaverine, a direct smooth muscle dilator, were impaired with the HM/LF diet in wild-type mice (30±3 versus 45±5%; P<0.05) but not DDAH1 Tg mice (45±7 versus 48±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.

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