Homocysteine impairs the nitric oxide synthase pathway -: Role of asymmetric dimethylarginine
Homocysteine impairs the nitric oxide synthase pathway -: Role of asymmetric dimethylarginine
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DOI：
10.1161/hc4601.098514
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发表时间：
2001-11-20
期刊：
影响因子：
37.8
通讯作者：
Cooke, JP
中科院分区：
文献类型：
--
作者：
Stühlinger, MC;Tsao, PS;Cooke, JP
高同型半胱氨酸血症是心血管疾病的一个公认的危险因素，它也损害内皮依赖性血管舒张。心血管疾病的许多其他风险因素可能部分通过升高血浆不对称二甲基精氨酸（ADMA）（一种内源性一氧化氮合酶抑制剂）水平来发挥其不良血管效应。因此，我们确定，如果同型半胱氨酸可以增加ADMA levels.Methods和结果，当内皮细胞或非血管细胞暴露于DL-同型半胱氨酸或其前体L-蛋氨酸，ADMA浓度在细胞培养基中的剂量和时间依赖性的方式增加。这种效应与二甲基精氨酸二甲基氨基水解酶（DDAH）的活性降低有关，DDAH是降解ADMA的酶。此外，同型半胱氨酸诱导的积累ADMA与减少一氧化氮合成的内皮细胞和猪主动脉段。抗氧化剂吡咯烷二硫代氨基甲酸酯保留DDAH活性并减少ADMA积累。此外，同型半胱氨酸，剂量依赖性地减少重组人DDAH在无细胞系统中的活性，这是由于同型半胱氨酸和DDAH.Conclusion-Homocysteine post-acetonally抑制DDAH酶活性，导致ADMA积累和抑制一氧化氮合成之间的直接相互作用的效果。这可以解释同型半胱氨酸损害内皮介导的一氧化氮依赖性血管舒张的已知效应。
Background-Hyperhomocysteinemia is a putative risk factor for cardiovascular disease, which also impairs endothelium-dependent vasodilatation. A number of other risk factors for cardiovascular disease may exert their adverse vascular effects in part by elevating plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Accordingly, we determined if homocysteine could increase ADMA levels.Methods and Results-When endothelial or nonvascular cells were exposed to DL-homocysteine or to its precursor L-methionine, ADMA concentration in the cell culture medium increased in a dose- and time-dependent fashion. This effect was associated with the reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Furthermore, homocysteine-induced accumulation of ADMA was associated with reduced nitric oxide synthesis by endothelial cells and segments of pig aorta. The antioxidant pyrrollidine dithiocarbamate preserved DDAH activity and reduced ADMA accumulation. Moreover, homocysteine, dose-dependently reduced the activity of recombinant human DDAH in a cell free system, an effect that was due to a direct interaction between homocysteine and DDAH.Conclusion-Homocysteine post-translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium-mediated nitric oxide-dependent vasodilatation.