Durand P, Lussier-Cacan S, Blache D
INSERM CJF 93-10, Laboratoire de Biochimie des Lipoprotéines, Faculté de Médecine, Université de Bourgogne, Dijon, France.
FASEB J. 1997 Nov;11(13):1157-68.
A moderate elevation of plasma homocysteine is a risk factor for atherosclerosis and arterial and veinous thrombosis. However, the mechanisms leading to vascular disorders are poorly understood because studies that have investigated the potential atherothrombogenicity of hyperhomocysteinemia in vivo are scarce. Using a rat model, we were the first to show that dietary folic acid deficiency, a major cause of basal hyperhomocysteinemia, is associated with enhanced macrophage-derived tissue factor and platelet activities. We proposed that an homocysteine-induced oxidative stress may account for this hypercoagulable state. To determine the true thrombogenicity of moderate hyperhomocysteinemia and better understand its etiology, we have carried out an acute methionine load in control and folate-deficient animals. When rats were fed the control diet, a transient fourfold increase in plasma homocysteine levels was observed 2 h after the methionine administration. As with prolonged dietary folic acid deficiency, this methionine load potentiated the platelet aggregation in response to thrombin and ADP as well as the thrombin-induced thromboxane synthesis. It also stimulated the basal and lipopolysaccharide-induced tissue factor activity of peritoneal macrophages. These prothrombotic effects were associated with an increased lipid peroxidation characterized by an elevation of plasma conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. When rats were fed a folic acid-deficient diet, the methionine load did not cause any further increase in plasma homocysteine concentration, platelet activation, macrophage tissue factor-dependent coagulation, or lipoperoxidation. Altogether, our data showed that the prethrombotic state due to both the altered remethylation and transsulfuration pathways resulted from the moderate elevation of circulating homocysteine. We conclude that moderate hyperhomocysteinemia plays a role in the development of a thrombogenic state that might be mediated by the occurrence of oxidative stress.
血浆同型半胱氨酸适度升高是动脉粥样硬化以及动静脉血栓形成的一个危险因素。然而，导致血管疾病的机制仍知之甚少，因为在体内研究高同型半胱氨酸血症潜在动脉粥样硬化血栓形成倾向的研究很匮乏。利用大鼠模型，我们首次表明，作为基础高同型半胱氨酸血症的主要原因，饮食中叶酸缺乏与巨噬细胞衍生的组织因子及血小板活性增强有关。我们提出，同型半胱氨酸诱导的氧化应激可能是这种高凝状态产生的原因。为了确定中度高同型半胱氨酸血症的真正血栓形成倾向并更好地理解其病因，我们对对照动物和叶酸缺乏动物进行了急性蛋氨酸负荷实验。当给大鼠喂食对照饮食时，在给予蛋氨酸后2小时观察到血浆同型半胱氨酸水平短暂升高四倍。与长期饮食中叶酸缺乏一样，这种蛋氨酸负荷增强了血小板对凝血酶和二磷酸腺苷的聚集反应以及凝血酶诱导的血栓素合成。它还刺激了腹膜巨噬细胞的基础组织因子活性以及脂多糖诱导的组织因子活性。这些促血栓形成作用与脂质过氧化增加有关，其特征是血浆共轭二烯、脂质氢过氧化物和硫代巴比妥酸反应性物质升高。当给大鼠喂食叶酸缺乏饮食时，蛋氨酸负荷并未导致血浆同型半胱氨酸浓度、血小板活化、巨噬细胞组织因子依赖性凝血或脂质过氧化进一步增加。总之，我们的数据表明，由于再甲基化和转硫途径改变导致的血栓前状态是由循环中同型半胱氨酸的适度升高引起的。我们得出结论，中度高同型半胱氨酸血症在可能由氧化应激发生介导的血栓形成状态的发展中起作用。
