Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA)
Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA)
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DOI：
10.1191/1358863x05vm605oa
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Maas, R
中科院分区：
文献类型：
--
作者：
Maas, R
内源性一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）的血浆浓度升高见于各种临床环境，包括肾衰竭、冠心病、高血压、糖尿病和先兆子痫。在健康人中，急性输注ADMA促进血管功能障碍，在小鼠中，慢性输注ADMA促进动脉粥样硬化的进展。因此，ADMA可能不仅是一个标志物，而且在心血管疾病中也是一个积极的参与者，这使其成为治疗干预的潜在靶点。本文综述了心血管药物、降糖药、激素替代疗法、抗氧化剂和维生素补充剂对血浆ADMA水平影响的现有数据，并进行了批判性讨论。我们评估的证据表明，药物治疗对血管功能的有益影响可以归因于ADMA水平的修改。为了开发更特异的降低ADMA的治疗方法，需要更好地了解导致心血管疾病患者血浆ADMA浓度升高的机制。ADMA是通过降解含有精氨酸残基的蛋白质内源性形成的，精氨酸残基已被S-腺苷甲硫氨酸依赖性甲基转移酶（PRMTS）甲基化。有两种主要消除途径：肾脏排泄和二甲基精氨酸二甲氨基水解酶（DDAH-1和-2）的酶降解。氧化应激导致PRMT表达上调和/或DDAH活性减弱已被认为是与ADMA升高相关的临床病症中的机制和可能的药物靶点。由于DDAH活性或能力的损害与血浆ADMA浓度的大幅增加相关，DDAH可能成为特定治疗干预的主要靶点。
Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are found in various clinical settings, including renal failure, coronary heart disease, hypertension, diabetes and preeclampsia. In healthy people acute infusion of ADMA promotes vascular dysfunction, and in mice chronic infusion of ADMA promotes progression of atherosclerosis. Thus, ADMA may not only be a marker but also an active player in cardiovascular disease, which makes it a potential target for therapeutic interventions. This review provides a summary and critical discussion of the presently available data concerning the effects on plasma ADMA levels of cardiovascular drugs, hypoglycemic agents, hormone replacement therapy, antioxidants, and vitamin supplementation. We assess the evidence that the beneficial effects of drug therapies on vascular function can be attributed to modification of ADMA levels. To develop more specific ADMA-lowering therapies, mechanisms leading to elevation of plasma ADMA concentrations in cardiovascular disease need to be better understood. ADMA is formed endogenously by degradation of proteins containing arginine residues that have been methylated by S-adenosylmethionine-dependent methyltransferases (PRMTS). There are two major routes of elimination: renal excretion and enzymatic degradation by the dimethylarginine dimethylaminohydrolases (DDAH-1 and -2). Oxidative stress causing upregulation of PRMT expression and/or attenuation of DDAH activity has been suggested as a mechanism and possible drug target in clinical conditions associated with elevation of ADMA. As impairment of DDAH activity or capacity is associated with substantial increases in plasma ADMA concentrations, DDAH is likely to emerge as a prime target for specific therapeutic interventions.