Association of asymmetric dimethylarginine and endothelial dysfunction
Association of asymmetric dimethylarginine and endothelial dysfunction
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DOI：
10.1515/cclm.2003.225
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发表时间：
2003-01-01
影响因子：
6.8
通讯作者：
Böger, RH
中科院分区：
文献类型：
--
作者：
Böger, RH
大量证据表明，内皮细胞在维持血管张力和结构方面起着至关重要的作用。一氧化氮(NO)是血管内皮细胞衍生的主要血管活性物质之一，是一种内源性抗动脉粥样硬化分子。硝基取代的精氨酸类似物作为酶活性部位的竞争性抑制剂，可以选择性地抑制NO的合成。其中一个类似物是不对称二甲基精氨酸(ADMA)，这是一种在人体血浆和尿液中发现的化合物，具有内源性一氧化氮合酶抑制物的活性。与ADMA相反，其区域异构体对称性二甲基精氨酸(SDMA)不抑制一氧化氮合酶。二甲基精氨酸分子中包含的甲基来自同型半胱氨酸/蛋氨酸途径中的中间体沙腺糖甲硫氨酸。有实验证据表明，同型半胱氨酸可能通过增加ADMA的形成而影响内皮依赖性血管功能。ADMA和SDMA都通过肾脏排泄从体内排出。此外，ADMA的代谢，而不是SDMA，通过二甲基精氨酸二甲氨基水解酶(DDAH)水解降解成瓜氨酸和二甲胺。来自实验研究的数据表明，ADMA在病理生理条件下的浓度(即315M)抑制血管NO的合成。ADMA可能是内皮细胞一氧化氮合酶活性的自分泌调节剂。当兔子被放入含有1%胆固醇的饮食中时，与对照动物相比，饮食干预后4周内ADMA水平升高。血浆ADMA浓度升高也存在于高胆固醇血症和高血压患者、慢性心力衰竭患者以及其他心血管疾病高危患者组。ADMA升高导致内皮功能障碍，临床表现为内皮依赖性血管扩张功能受损，血小板高度聚集，单核细胞黏附增强。最近的前瞻性研究表明，内皮功能障碍预示着未来心血管事件的风险增加。根据这些观察，我们和其他人发现了ADMA是一种新的心血管危险因素的证据。
There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endotheliumderived vasoactive mediators is nitric oxide (NO), which has been characterized as an endogenous antiatherosclerotic molecule. Synthesis of NO can be selectively inhibited by guanidinosubstituted analogs of Larginine, which act as competitive inhibitors at the active site of the enzyme. One such analog is asymmetric dimethylarginine (ADMA), a compound that has been found in human plasma and urine and exerts the activity of an endogenous inhibitor of NO synthase. In contrast to ADMA, its regioisomer symmetric dimethylarginine (SDMA) does not inhibit NO synthase. The methyl groups contained within the dimethylarginine molecules are derived from Sadenosylmethionine, an intermediate in the homocysteine/methionine pathway. There is experimental evidence that homocysteine may affect endotheliumdependent vascular function by increasing the formation of ADMA. Both ADMA and SDMA are eliminated from the body by renal excretion. In addition, the metabolism of ADMA, but not SDMA, occurs via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Data from experimental studies suggest that ADMA inhibits vascular NO elaboration at concentrations found in pathophysiological conditions (i.e., 315 M). ADMA likely acts as an autocrine regulator of endothelial NO synthase activity. When rabbits are placed on a diet enriched with 1% cholesterol, ADMA levels are increased within 4 weeks of dietary intervention as compared to control animals. Elevated plasma concentrations of ADMA are also present in hypercholesterolemic and hypertensive patients, in patients with chronic heart failure, and in other patient groups at high risk of developing cardiovascular disease. Elevation of ADMA induces dysfunction of the endothelium, which becomes clinically evident by impaired endotheliumdependent vasodilation, hyperaggregability of platelets, and enhanced monocyte adhesion. Recent prospective studies suggest that endothelial dysfunction indicates an increased risk of future cardiovascular events. In line with these observations, we and others found evidence that ADMA is a novel cardiovascular risk factor.