Homocysteine: Vascular Biochemistry and Metabolism

描述(由申请人提供)：高同型半胱氨酸血症是心血管疾病、认知功能障碍、妊娠并发症和骨质疏松症的可改变的独立危险因素。同型半胱氨酸诱导的内皮细胞功能障碍可能与这一组不同的病理联系在一起。我们的研究主要集中在：1)同型半胱氨酸的血管生物化学；2)同型半胱氨酸在培养的人主动脉内皮细胞中的转运机制；3)同型半胱氨酸对蛋白质半胱氨酸残基的分子靶向。硫醇-二硫键交换是同型半胱氨酸在循环中的存在形式。半胱氨酸转运体在血管内皮细胞中介导同型半胱氨酸的输入。有证据表明，同型半胱氨酸靶向与血管细胞功能障碍有关。长期目标是了解同型半胱氨酸加速动脉粥样硬化形成的机制，并开发改进的干预策略，在高危受试者和常规治疗无效的受试者(例如终末期肾脏疾病)中降低血浆总同型半胱氨酸。我们的中心假设是：1)同型半胱氨酸是早期动脉粥样硬化的介体，但却成为晚期动脉粥样硬化的标志物(我们称之为高同型半胱氨酸血症的“介体标记物假说”)；2)单核细胞趋化蛋白1和其他促炎细胞因子是由同型半胱氨酸通过激活核因子-kB在动脉粥样硬化早期诱导的；3)同型半胱氨酸因果关系的基本机制是分子靶向；以及，4)通过初级干预降低同型半胱氨酸水平将减少与高同型半胱氨酸血症相关的死亡率和发病率。我们的具体目标是：1)研究蛋白质同型半胱氨酸化的机制和功能后果；2)研究同型半胱氨酸及其二硫代异构体在血管细胞中的运输和代谢；3)鉴定同型半胱氨酸靶向的细胞内蛋白质(如金属硫蛋白)，以及靶向蛋白质的功能丧失如何导致血管细胞功能障碍。1998年1月完成的用叶酸强化美国人饮食的计划在减少高同型半胱氨酸血症、神经管畸形以及可能因中风和心脏病发作而导致的死亡率方面产生了深远的影响。通过更好地了解同型半胱氨酸的运输、新陈代谢以及同型半胱氨酸对我们循环系统的不利影响，可能会对公众健康产生额外的好处。

DESCRIPTION (provided by applicant): Hyperhomocysteinemia is a modifiable, independent risk factor for cardiovascular disease, cognitive dysfunction, complications of pregnancy, and osteoporosis. Homocysteine-induced endothelial cell dysfunction may link this diverse group of pathologies. Our research has focused on: 1) the vascular biochemistry of homocysteine; 2) the mechanism of homocysteine transport in cultured human aortic endothelial cells; and, 3) the molecular targeting of protein cysteine residues by homocysteine. Thiol-disulfide exchange accounts for the forms of homocysteine in circulation. Cysteine transporters mediate homocysteine import in the vascular endothelium. Evidence is provided that links homocysteine targeting to vascular cell dysfunction. The long-term objectives are to understand the mechanism of homocysteine-accelerated atherogenesis and to develop improved interventional strategies that will lower plasma total homocysteine in high-risk subjects and in subjects who are refractory to conventional therapy (e.g., end-stage renal disease). Our central hypotheses are: 1) homocysteine is a mediator of early atherogenesis but becomes a marker in advanced atherosclerosis (we call this the "mediator ?>? marker hypothesis" of hyperhomocysteinemia); 2) monocyte chemoattractant protein 1 and other pro-inflammatory cytokines are induced by homocysteine in early atherogenesis by a mechanism involving the activation of NF-kB; 3) the fundamental mechanism underlying homocysteine causality is molecular targeting; and, 4) homocysteine-lowering by primary intervention will reduce mortality and morbidity associated with hyperhomocysteinemia. Our specific aims are: 1) to study the mechanism of protein homocysteinylation and functional consequences; 2) to study the transport and metabolism of homocysteine and its disulfide congeners in vascular cells; and, 3) to identify intracellular proteins (e.g., metallothionein) targeted by homocysteine and how loss of function of targeted proteins leads to vascular cell dysfunction. The program to fortify the American diet with folic acid, completed in January, 1998, has had a profound effect on reducing the incidence of hyperhomocysteinemia, neural tube defects and, possibly, mortality due to stroke and heart attack. Additional public health benefits are likely by gaining a better understanding of homocysteine transport, metabolism and the adverse effects of homocysteine on our circulatory system.