Overexpression of Dimethylarginine Dimethylaminohydrolase Protects Against Cerebral Vascular Effects of Hyperhomocysteinemia

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 mu mol/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 mu mol/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. (Circ Res. 2010;106:551-558.)