Influence of hyperhomocysteinemia on the cellular redox state - Impact on homocysteine-induced endothelial dysfunction
Influence of hyperhomocysteinemia on the cellular redox state - Impact on homocysteine-induced endothelial dysfunction
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DOI：
10.1515/cclm.2003.223
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发表时间：
2003-01-01
影响因子：
6.8
通讯作者：
Loscalzo, J
中科院分区：
文献类型：
--
作者：
Weiss, N;Heydrick, SJ;Loscalzo, J
高同型半胱氨酸血症是动脉粥样硬化发展的独立危险因素。越来越多的证据表明氧化应激是同型半胱氨酸对血管系统有害作用的原因。高半胱氨酸水平升高可能导致通过涉及一氧化氮合酶的生化机制产生的超氧化物增加，以及在较小程度上通过循环中高半胱氨酸和其他氨基硫醇的化学氧化增加。由此产生的超氧化物水平的增加被细胞抗氧化酶如细胞谷胱甘肽过氧化物酶或细胞外超氧化物歧化酶的功能中的同型半胱氨酸依赖性改变进一步放大。血管超氧化物水平升高的一个直接临床后果是血管舒张信使一氧化氮的失活，导致内皮功能障碍。超氧化物歧化酶或4，5-二羟基苯1，3-二磺酸盐（Tiron）清除超氧阴离子可逆转高同型半胱氨酸血症动物模型和与同型半胱氨酸孵育的离体主动脉环的内皮功能障碍。类似地，在轻度高同型半胱氨酸血症的动物模型中，同型半胱氨酸诱导的内皮功能障碍也通过增加内源性抗氧化剂谷胱甘肽的浓度或过表达细胞谷胱甘肽过氧化物酶来逆转。综上所述，这些研究结果强烈表明，同型半胱氨酸的不良血管效应至少部分介导的一氧化氮的氧化失活。
Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteines deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteinedependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteineinduced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.