Asymmetric dimethylarginine, and endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as a novel cardiovascular risk factor
Asymmetric dimethylarginine, and endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as a novel cardiovascular risk factor
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DOI：
10.1093/jn/134.10.2842s
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发表时间：
2004-10-01
影响因子：
4.2
通讯作者：
Böger, RH
中科院分区：
文献类型：
--
作者：
Böger, RH
有大量证据表明，内皮细胞在维持血管张力和结构中起着至关重要的作用。一氧化氮（NO）是内皮细胞产生的主要血管活性介质之一。不对称二甲基精氨酸（ADMA）是一种内源性竞争性NO合酶抑制剂。ADMA在病理生理条件下抑制血管NO的产生; ADMA在动脉内输注时也会引起局部血管收缩。因此，升高的ADMA水平可以解释“L-精氨酸悖论”，即，观察到补充外源性L-精氨酸改善了体内NO介导的血管功能，尽管其基线血浆浓度比体外分离纯化的内皮NO合酶的Michaelis-Menten常数K-m高约25倍。与ADMA相关的生物化学和生理学途径已被充分理解：二甲基精氨酸是甲基化蛋白质降解的结果;甲基来自S-腺苷甲硫氨酸。ADMA及其区域异构体对称二甲基精氨酸通过肾脏排泄从体内消除，而只有ADMA通过二甲基精氨酸二甲氨基水解酶（DDAH）水解降解为瓜氨酸和二甲胺代谢。因此，DDAH活性和/或表达可能有助于各种疾病中内皮功能障碍的发病机制。在患有高胆固醇血症、动脉粥样硬化、高血压、慢性肾衰竭和慢性心力衰竭的人中，血浆ADMA水平升高。ADMA水平升高与NO合成减少相关，这通过受损的内皮依赖性血管舒张来评估。在几项前瞻性和横断面研究中，ADMA逐渐成为心血管风险的标志物。随着对ADMA在心血管疾病发病机制中作用的认识不断增加，ADMA正成为药物干预的目标。在目前正在测试的其他潜在策略中，L-精氨酸的给药已被证明可改善高ADMA水平受试者的内皮依赖性血管功能。最后，ADMA最近获得了临床重要性，因为一些研究表明ADMA是一个独立的心血管危险因素。
There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase. ADMA inhibits vascular NO production in concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intraarterially. Thus, elevated ADMA levels may explain the "L-arginine paradox," i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Michaelis-Menten constant K-m of the isolated, purified endothelial NO synthase in vitro. The biochemical and physiological pathways related to ADMA are well understood: Dimethylarginines are the result of degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, symmetric dimethylarginine, are eliminated from the body by renal excretion, whereas only ADMA is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. Plasma ADMA levels are increased in humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic interventions. Among other potential strategies that are currently being tested, administration of L-arginine has been shown to improve endothelium-dependent vascular functions in subjects with high ADMA levels. Finally, ADMA has gained clinical importance recently because several studies have shown that ADMA is an independent cardiovascular risk factor.