Stamler J S, Osborne J A, Jaraki O, Rabbani L E, Mullins M, Singel D, Loscalzo J
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
J Clin Invest. 1993 Jan;91(1):308-18. doi: 10.1172/JCI116187.
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.
同型半胱氨酸水平升高与动脉粥样硬化和血栓形成风险增加相关。同型半胱氨酸巯基的反应性与这种风险增加背后的分子机制有关。越来越多令人信服的证据表明，硫醇在一氧化氮（NO）和内皮源性舒张因子（EDRF）存在的情况下发生反应，形成具有强大血管舒张和抗血小板作用的S-亚硝基硫醇化合物。因此，我们推测同型半胱氨酸的S-亚硝基化会赋予该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，刺激分泌EDRF的内皮细胞短暂（15分钟）暴露于同型半胱氨酸会导致形成S-NO-同型半胱氨酸，一种强大的抗血小板剂和血管舒张剂。与同型半胱氨酸不同，S-NO-同型半胱氨酸不支持过氧化氢生成，也不会转化为同型半胱氨酸硫内酯，这些反应产物被认为会导致内皮毒性。这些结果表明，正常内皮通过释放EDRF和形成加合物S-NO-同型半胱氨酸来调节同型半胱氨酸的潜在不良影响。同型半胱氨酸的不良血管特性可能是由于功能逐渐失调的内皮细胞产生的NO与同型半胱氨酸水平之间的渐进性失衡，导致无法维持S-NO的形成。
