Nebivolol reduces asymmetric dimethylarginine in endothelial cells by increasing dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression and activity
Nebivolol reduces asymmetric dimethylarginine in endothelial cells by increasing dimethylarginine dimethylaminohydrolase 2 (DDAH2) expression and activity
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DOI：
10.1016/j.phrs.2007.09.015
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发表时间：
2007-12-01
影响因子：
9.3
通讯作者：
Cominacini, Luciano
中科院分区：
文献类型：
--
作者：
Garbin, Ulisse;Fratta Pasini, Anna;Cominacini, Luciano
据报道，不对称二甲基精氨酸（ADMA）通过抑制内皮NO合成酶（eNOS）活性来影响内皮细胞中一氧化氮（NO）的合成，并导致人类内皮功能障碍。本研究在人脐静脉内皮细胞（HUVECs）中进行，以评估奈比洛尔（一种选择性β 1-肾上腺素能受体拮抗剂）对ADMA浓度和调节ADMA分解代谢的二甲精氨酸二甲氨基水解酶（DDAH2）的影响。奈比洛尔呈剂量依赖性降低ADMA/对称二甲基精氨酸（SDMA）比值（p < 0.01 ~ < 0.001）。DDAH2 mRNA （P从< 0.01到< 0.001）、蛋白质表达（P从< 0.01到< 0.001）和活性（P从< 0.01到< 0.001）的剂量依赖性增加也与此相似。小干扰RNA （small interference RNA, siRNA）介导的DDAH2敲低可消除奈比洛尔诱导的DDAH2表达改变（p < 0.001）和ADMA/SDMA比值（p < 0.001）。综上所述，本研究结果表明奈比洛尔通过增加DDAH2的表达和活性来降低ADMA浓度。我们的体外研究结果描述了奈比洛尔的一种新的血管作用，并清楚地确定了这种化合物是第一种调节内皮细胞中DDAH2的降压药。(c) 2007 Elsevier Ltd.版权所有。
Asymmetric dimethylarginine (ADMA) has been reported to affect the synthesis of nitric oxide (NO) in endothelial cells by inhibiting endothelial NO synthase (eNOS) activity and to cause endothelial dysfunction in humans. This study was conducted in human umbilical vein endothelial cells (HUVECs) to evaluate the effect of nebivolol, a selective beta 1-adrenergic receptor antagonist, on ADMA concentration and on dimethylarginine dimethylaminohydrolase (DDAH2), the enzyme that regulates ADMA catabolism. Nebivolol dose-dependently decreased ADMA/symmetric dimethylarginine (SDMA) ratio (p from < 0.01 to < 0.001). This was parallelled by a dose-dependent increase in DDAH2 mRNA (P from < 0.01 to < 0.001) and protein expression (p from < 0.01 to < 0.001) and activity (p from < 0.01 to < 0.001). The small interference RNA (siRNA)-mediated knockdown of DDAH2 abolished the modification of DDAH2 expression (p < 0.001) and ADMA/SDMA ratio (p < 0.001) induced by nebivolol. In conclusion, the results of this study demonstrate that nebivolol reduces ADMA concentration by increasing DDAH2 expression and activity. Our in vitro findings describe a novel vascular effect of nebivolol and clearly identify this compound as the first antihypertensive agent that modulates DDAH2 in endothelial cells. (c) 2007 Elsevier Ltd. All rights reserved.