HOMOCYSTEINE--VASCULAR BIOCHEMISTRY AND METABOLISM

高同型半胱氨酸血症和心血管疾病之间的关系是 很好地建立了。 发病率和死亡率的主要原因 常染色体隐性遗传性高胱氨酸尿症是早产 动脉粥样硬化伴动脉和静脉血栓形成。最近的几 涉及3,000多名患者的临床研究表明， 轻度至轻度高同型半胱氨酸血症与 冠状动脉疾病、脑血管疾病和外周血管疾病 闭塞性疾病，独立于传统的风险因素， 高血压、吸烟、高脂血症和糖尿病。早期工作，由 内皮细胞对损伤的反应假说表明， 同型半胱氨酸和同型半胱氨酸硫内酯的超生理水平 对血管内皮细胞有损伤和细胞毒性。然而，在这方面， 对高半胱氨酸诱导的细胞毒性的机制知之甚少， 甚至也不知道同型半胱氨酸在内皮细胞中是如何代谢的。此外，委员会认为， 实际上，我们对它们之间的化学相互作用一无所知。 同型半胱氨酸和血浆蛋白。我们的工作将集中在生物化学 和同型半胱氨酸在血管系统中的代谢， 同型半胱氨酸水平升高可能会导致动脉粥样硬化， 内皮细胞的促血栓形成功能。 我们假设 主动脉和冠状动脉内皮细胞对升高的 同型半胱氨酸，因为转硫途径是无活性的， 细胞此外，升高的同型半胱氨酸诱导表达 粘附分子，从而促进单核细胞募集。具体 这项研究的目的是： 1)研究同型半胱氨酸和特异性 使用体外模型，使我们能够确定 他们的同型半胱氨酸结合能力，并分析交换 同型半胱氨酸和蛋白结合半胱氨酸之间的动力学。隔离， 表征和鉴定同型半胱氨酸的内源性载体， 正常和高同型半胱氨酸血症血浆; 2)以确定同型半胱氨酸代谢途径在培养的人 通过测量钴胺素（B 12）依赖性蛋氨酸的主动脉内皮细胞 合成酶、吡哆醛依赖性胱硫醚（3-合成酶和 亚甲基四氢叶酸还原酶，并将这些测量结果与 新鲜人冠状动脉标本中的酶活性 心 3)以确定生理浓度的同型半胱氨酸对 对内皮细胞功能，特别是促进单核细胞 粘附培养的主动脉内皮细胞，并获得一个机制， 理解这一现象。 这些研究将提供有价值的新见解，对血管 同型半胱氨酸的生化和代谢，并可能提出一个理由， 用于治疗高同型半胱氨酸血症。

The association between hyperhomocysteinemia and cardiovascular disease is well established. The principal cause of morbidity and mortality in autosomal recessive inheritable homocystinuria is premature atherosclerosis with arterial and venous thrombosis. Several recent clinical studies involving over 3,000 patients have shown a relationship between slight to mild hyperhomocysteinemia and the development of coronary artery disease, cerebrovascular disease and peripheral vascular occlusive disease, independent of traditional risk factors such as hypertension, smoking, hyperlipidemia and diabetes. Early work, guided by the endothelial response-to-injury hypothesis, showed that high supraphysiological levels of homocysteine and homocysteine thiolactone were injurious and cytotoxic to vascular endothelial cells. However, little is known about the mechanism of homocysteine-induced cytotoxicity, or even how homocysteine is metabolized in endothelial cells. Furthermore, practically nothing is known about the chemical interactions between homocysteine and plasma proteins. Our work will focus on the biochemistry and metabolism of homocysteine in the vascular system and the effect that elevated levels of homocysteine might have on proatherogenic and prothrombogenic functions of endothelial cells. We hypothesize that aortic and coronary artery endothelial cells are sensitive to elevated homocysteine because the transsulfuration pathway is inactive in these cells. Furthermore elevated homocysteine induces the expression of adhesion molecules, thereby promoting monocyte recruitment. The specific aims of this study are: 1) to investigate the interactions between homocysteine and specific plasma proteins using in vitro models that will allow us to determine their binding capacity for homocysteine and to analyze the exchange kinetics between homocysteine and protein-bound cysteine. Isolate, characterize and identify the endogenous carriers of homocysteine in normal and hyperhomocysteinemic plasma; 2) to determine the pathways of homocysteine metabolism in cultured human aorta endothelial cells by measuring cobalamin (B 12)-dependent methionine synthase, pyridoxal-dependent cystathionine (3-synthase and methylenetetrahydrofolate reductase and to compare these measurements with enzyme activities in fresh preparations of coronary arteries from human hearts 3) to establish the effect of physiological concentrations of homocysteine on endothelial cell function, especially the promotion of monocytic adhesion to cultured aortic endothelial cells, and to gain a mechanistic understanding of this phenomenon. These studies will provide valuable new insights on the vascular biochemistry and metabolism of homocysteine and may suggest a rationale for the treatment of hyperhomocysteinemia.