Surdacki Andrzej
2nd Department of Cardiology, Jagiellonian University, Cracow, Poland.
Cardiovasc Hematol Agents Med Chem. 2008 Oct;6(4):302-11. doi: 10.2174/187152508785909429.
Dimethylated L-arginine analogs have been attracting the attention of both basic researchers and clinicians for 15 years since 1992 when Vallance et al. were first to observe several fold elevations of asymmetric and symmetric dimethyl-L-arginine levels (ADMA and SDMA, respectively) in plasma of hemodialyzed patients. ADMA - in contrast to SDMA - competes with L-arginine at the level of NO synthase with consequent inhibition of NO generation. Later studies have revealed excessive ADMA accumulation in the presence of atherosclerotic risk factors and endothelial dysfunction even in patients free of clinical evidence of atherosclerosis. Moreover, ADMA concentrations were elevated also in proportion to the severity of carotid, coronary and peripheral atherosclerosis. Additionally, in vitro studies have shown the ability of proinflammatory cytokines and oxidized low-density lipoproteins to increase liberation of ADMA by cultured endothelial cells. This evidence has provoked a hypothesis that ADMA may accelerate atherogenesis by inhibition of endothelial NO synthase. Indeed, ADMA concentration proved to be an independent adverse outcome predictor in end-stage renal disease and in coronary artery disease. On the other hand, it remains an intriguing issue how ADMA is able to exert any biological effects in the presence of saturating L-arginine concentrations which are well above the Michaelis-Menten constant of endothelial NO synthase for L-arginine. Recent years have brought novel fascinating findings in the field of research on dimethylated L-arginine analogs. First, ADMA has been shown to accelerate replicative senescence of endothelial cells via inhibition of the activity of telomerase, an enzyme counteracting telomere attrition, a molecular "clock". Second, ADMA impairs the mobilization and activity of bone marrow-derived endothelial progenitor cells that participate in continuous endothelial renewal and neovascularization of ischemic tissues. Third, SDMA - previously considered an inactive stereoisomer of ADMA - has been demonstrated to inhibit NO synthesis via competition with L-arginine uptake by endothelial cells. As SDMA rises in earlier stages of renal dysfunction than ADMA, it may contribute to excessive cardiovascular morbidity in chronic kidney disease.
自1992年瓦伦斯等人首次观察到血液透析患者血浆中不对称和对称二甲基-L-精氨酸水平（分别为ADMA 和 SDMA）升高数倍以来，二甲基化L-精氨酸类似物在15年里一直吸引着基础研究人员和临床医生的关注。与SDMA不同，ADMA在一氧化氮合酶水平上与L-精氨酸竞争，从而抑制一氧化氮的生成。后来的研究表明，即使在没有动脉粥样硬化临床证据的患者中，在存在动脉粥样硬化危险因素和内皮功能障碍的情况下，也会出现ADMA过度蓄积。此外，ADMA浓度也与颈动脉、冠状动脉和外周动脉粥样硬化的严重程度成正比升高。此外，体外研究表明，促炎细胞因子和氧化型低密度脂蛋白能够增加培养的内皮细胞释放ADMA。这些证据引发了一个假说，即ADMA可能通过抑制内皮一氧化氮合酶来加速动脉粥样硬化的发生。事实上，ADMA浓度被证明是终末期肾病和冠状动脉疾病中独立的不良结局预测指标。另一方面，在L-精氨酸浓度饱和（远高于内皮一氧化氮合酶对L-精氨酸的米氏常数）的情况下，ADMA如何能够发挥任何生物学效应仍然是一个有趣的问题。近年来，在二甲基化L-精氨酸类似物的研究领域有了一些新奇有趣的发现。首先，ADMA已被证明可通过抑制端粒酶的活性来加速内皮细胞的复制性衰老，端粒酶是一种对抗端粒磨损（一种分子“时钟”）的酶。其次，ADMA会损害骨髓来源的内皮祖细胞的动员和活性，这些细胞参与缺血组织的持续内皮更新和新血管形成。第三，SDMA——以前被认为是ADMA的无活性立体异构体——已被证明可通过与内皮细胞摄取L-精氨酸竞争来抑制一氧化氮合成。由于SDMA在肾功能障碍的早期阶段比ADMA升高得更早，它可能导致慢性肾病患者心血管疾病发病率过高。
