ADVERSE VASCULAR EFFECTS OF HOMOCYSTEINE ARE MODULATED BY ENDOTHELIUM-DERIVED RELAXING FACTOR AND RELATED OXIDES OF NITROGEN
ADVERSE VASCULAR EFFECTS OF HOMOCYSTEINE ARE MODULATED BY ENDOTHELIUM-DERIVED RELAXING FACTOR AND RELATED OXIDES OF NITROGEN
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DOI：
10.1172/jci116187
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发表时间：
1993-01-01
影响因子：
15.9
通讯作者：
LOSCALZO, J
中科院分区：
文献类型：
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作者：
STAMLER, JS;OSBORNE, JA;LOSCALZO, J
同型半胱氨酸水平升高与动脉粥样硬化和血栓形成的风险增加有关。同型半胱氨酸的巯基的反应性被认为是导致这种风险增加的分子机制之一。也有越来越令人信服的证据表明，硫醇在一氧化氮(NO)和内皮衍生松弛因子(EDRF)的存在下反应生成S亚硝硫醇，这是一种具有强大的血管扩张和抗血小板作用的化合物。因此，我们假设同型半胱氨酸的S亚硝化反应将赋予硫醇这些有益的生物活性，同时减弱其致病性。我们发现，内皮细胞长时间(>；3小时)暴露于同型半胱氨酸会导致EDRF反应受损。相比之下，刺激内皮细胞分泌EDRF的短暂(15分钟)暴露于同型半胱氨酸会导致S-NO-同型半胱氨酸的形成，这是一种有效的抗血小板药物和血管扩张剂。与同型半胱氨酸不同，S-NO-同型半胱氨酸不支持过氧化氢的产生，也不会转化为同型半胱氨酸硫内酯，后者被认为是导致内皮毒性的反应产物。这些结果提示，正常血管内皮细胞通过释放内皮细胞因子，形成S-NO-同型半胱氨酸加合物来调节同型半胱氨酸的潜在副作用。同型半胱氨酸的不良血管特性可能是由于进行性功能障碍的内皮细胞产生NO和同型半胱氨酸水平之间的渐进性失衡而导致无法维持S-NO的形成。
Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine.