Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia.
Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia.
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DOI：
10.1161/circresaha.109.200360
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发表时间：
2010-02-19
影响因子：
20.1
通讯作者：
Lentz SR
中科院分区：
文献类型：
--
作者：
Rodionov RN;Dayoub H;Lynch CM;Wilson KM;Stevens JW;Murry DJ;Kimoto M;Arning E;Bottiglieri T;Cooke JP;Baumbach GL;Faraci FM;Lentz SR
高同型半胱氨酸血症是一种心血管危险因素，与一氧化氮合酶抑制剂不对称二甲基精氨酸 (ADMA) 相关。使用过度表达 ADMA 水解酶二甲基精氨酸二甲氨基水解酶-1 (DDAH1) 的转基因小鼠，我们测试了以下假设：DDAH1 的过度表达可防止高同型半胱氨酸血症中脑小动脉的不良结构和功能变化。使用高蛋氨酸/低叶酸 (HM/LF) 饮食在 DDAH1 转基因 (DDAH1 Tg) 小鼠和野生型同窝小鼠中诱导高同型半胱氨酸血症。与对照饮食相比，喂食 HM/LF 饮食的野生型和 DDAH1 Tg 小鼠的血浆总同型半胱氨酸升高了约 3 倍（P<0.001）。与野生型小鼠相比，DDAH1 Tg 小鼠的血浆 ADMA 降低约 40% (P<0.001)，无论饮食如何。与对照饮食相比，HM/LF饮食减少了野生型（12±2 vs. 29±3%；P<0.001）和DDAH1 Tg（14±3 vs. 28±2%；P<0.001）小鼠脑小动脉中内皮依赖性扩张至10 µmol/L乙酰胆碱。野生型小鼠对 10 µmol/L 罂粟碱（一种直接平滑肌扩张剂）的反应因 HM/LF 饮食而受损（30±3 vs. 45±5%；P<0.05），但 DDAH1 Tg 小鼠则不然（45±7 vs. 48±6%）。 DDAH1 Tg 小鼠也能免受脑小动脉肥大的影响（P<0.05），但不能免受 HM/LF 饮食诱导的加速颈动脉血栓形成的影响。 DDAH1 的过度表达可防止高同型半胱氨酸血症引起的脑小动脉结构和血管肌肉功能的改变。
Hyperhomocysteinemia is a cardiovascular risk factor that is associated with the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). 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. 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 vs. 29±3%; P<0.001) and DDAH1 Tg (14±3 vs. 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 vs. 45±5%; P<0.05) but not DDAH1 Tg mice (45±7 vs. 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. Overexpression of DDAH1 protects from hyperhomocysteinemia-induced alterations in cerebral arteriolar structure and vascular muscle function.