Vascular endothelial-specific dimethylarginine dimethylaminohydrolase-1-deficient mice reveal that vascular endothelium plays an important role in removing asymmetric dimethylarginine.
Vascular endothelial-specific dimethylarginine dimethylaminohydrolase-1-deficient mice reveal that vascular endothelium plays an important role in removing asymmetric dimethylarginine.
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DOI：
10.1161/circulationaha.108.819912
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发表时间：
2009-12-01
期刊：
影响因子：
37.8
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Hu X;Xu X;Zhu G;Atzler D;Kimoto M;Chen J;Schwedhelm E;Lüneburg N;Böger RH;Zhang P;Chen Y
不对称甲基精氨酸抑制一氧化氮（NO）合成酶（NOS）活性，从而减少NO的产生。二甲基精氨酸二甲基氨基水解酶1 （DDAH1）降解不对称甲基精氨酸。我们之前已经证明，在心脏中，DDAH1主要在血管内皮细胞中表达。由于早期的研究表明，DDAH1缺失的小鼠具有胚胎致死性，我们推测，选择性血管内皮DDAH1缺失的小鼠品系（endod -DDAH1 - / -）会在许多组织中很大程度上消除DDAH1的组织表达，但可能避免胚胎致死性。通过LoxP/Cre方法，我们生成了内切- ddah1 - / -小鼠。与野生型仔鼠相比，内源性ddah1 - / -小鼠在生长发育方面没有明显缺陷。DDAH1在肾、肺、脑、肝等脏器中的表达显著降低，说明DDAH1主要分布在血管内皮细胞中。内源性ddah1−/−小鼠的血浆（内源性ddah1−/−小鼠为1.41μM，对照组为0.69μM）、肾脏、肺和肝脏的不对称甲基精氨酸浓度显著升高，并伴有收缩压显著升高（野生型为132 mmHg，野生型为113 mmHg）。内切ddah1 - / -小鼠也表现出乙酰胆碱诱导的一氧化氮生成和离体主动脉环血管舒张的显著减弱。我们的研究表明，DDAH1在血管内皮中高表达，内皮中DDAH1在调节血压中起重要作用。在不对称甲基精氨酸广泛产生于多种类型细胞的背景下，DDAH1在血管内皮中的强表达首次证明血管内皮可能是主动处置其他类型细胞产生的有毒生化分子的重要部位。
Asymmetric methylarginines inhibit nitric oxide (NO) synthase (NOS) activity and thereby decrease NO production. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) degrades asymmetric methylarginines. We previously demonstrated that in the heart DDAH1 is predominantly expressed in vascular endothelial cells. Since an earlier study showed that mice with global DDAH1 deficiency was embryonic lethal, we speculate that a mouse strain with selective vascular endothelial DDAH1 deficiency (endo-DDAH1−/−) would largely abolish tissue DDAH1 expression in many tissues but possibly avoid embryonic lethality. By using the LoxP/Cre approach, we generated the endo-DDAH1−/− mice. The endo-DDAH1−/− mice had no apparent defect in growth or development as compared with wild type littermates. DDAH1 expression was greatly reduced in kidney, lung, brain, and liver, indicating that in these organs DDAH1 is mainly distributed in vascular endothelial cells. The endo-DDAH1−/− mice showed a significant increase of asymmetric methylarginine concentration in plasma (1.41μM in the endo-DDAH1−/− vs. 0.69μM in the control mice), kidney, lung and liver, which was associated with significantly increased systolic blood pressure (132 mmHg vs. 113 mmHg in wild type). The endo-DDAH1−/− mice also exhibited significantly attenuated acetylcholine-induced NO production and vessel relaxation in isolated aortic rings. Our study demonstrates that DDAH1 is highly expressed in vascular endothelium, and that endothelial DDAH1 plays an important role in regulating blood pressure. In the context that asymmetric methylarginines are broadly produced by many type of cells, the strong DDAH1 expression in vascular endothelium demonstrates for the first time that vascular endothelium can be an important site to actively dispose of toxic biochemical molecules produced by other types of cells.