Dayal Sanjana, Lentz Steven R
Department of Internal Medicine, University of Iowa, Iowa City 52242, USA.
Vasc Med. 2005 Jul;10 Suppl 1:S27-33. doi: 10.1191/1358863x05vm599oa.
Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Like many other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). The molecular mechanisms responsible for decreased NO bioavailability in hyperhomocysteinemia are incompletely understood, but emerging evidence suggests that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may be a key mediator. Homocysteine is produced during the synthesis of ADMA and can alter ADMA metabolism by inhibiting dimethylarginine dimethylaminohydrolase (DDAH). Several animal and clinical studies have demonstrated a strong association between plasma total homocysteine, plasma ADMA, and endothelial dysfunction. These observations suggest a model in which elevation of ADMA may be a unifying mechanism for endothelial dysfunction during hyperhomocysteinemia. The recent development of transgenic mice with altered ADMA metabolism should provide further mechanistic insights into the role of ADMA in hyperhomocysteinemia.
高同型半胱氨酸血症是心血管疾病和中风的一个危险因素。与许多其他心血管危险因素一样，高同型半胱氨酸血症会因内皮源性一氧化氮（NO）的生物利用度受损而导致内皮功能障碍。高同型半胱氨酸血症中导致NO生物利用度降低的分子机制尚未完全明确，但新出现的证据表明，不对称二甲基精氨酸（ADMA），一种NO合酶的内源性抑制剂，可能是关键介质。同型半胱氨酸在ADMA的合成过程中产生，并且可以通过抑制二甲基精氨酸二甲氨基水解酶（DDAH）来改变ADMA代谢。多项动物和临床研究表明，血浆总同型半胱氨酸、血浆ADMA与内皮功能障碍之间存在密切关联。这些观察结果提示了一种模型，其中ADMA升高可能是高同型半胱氨酸血症期间内皮功能障碍的统一机制。最近对ADMA代谢改变的转基因小鼠的研究进展应该能为ADMA在高同型半胱氨酸血症中的作用提供进一步的机制性见解。
