HOMOCYSTEINE--VASCULAR BIOCHEMISTRY AND METABOLISM

高同型半胱氨酸血症是心血管疾病的独立危险因素 疾病，但对血管生物化学和 同型半胱氨酸的代谢或其在动脉粥样硬化形成中所起的作用。为 在过去的三年里，我们的实验室一直在关注这些问题。我们 已经表明血管细胞和组织具有有限的能力 代谢同型半胱氨酸。分解代谢的跨硫途径出现 是无效的，而替代的再甲基化途径不是 表达。因此，依赖叶酸/B12的重新甲基化可能是唯一的 血管系统中可用于维持低血压的途径 细胞内同型半胱氨酸水平。我们假设总体上 这一途径的效率将取决于辅因子的可用性。 和酶的功能。为了检验这一假设，我们已经建立了 探索基因-营养相互作用的细胞模型。这些研究 将重点放在亚甲基四氢叶酸还原酶和蛋氨酸 合酶，以及在体内驱动同型半胱氨酸重新甲基化的酶 血管细胞。具有共同基因纯合子的个体 多态(在许多人群中患病率为15%) 还原酶基因似乎具有显著更高的血浆总水平 同型半胱氨酸水平，如果加上低叶酸状态。因为他们的 代谢同型半胱氨酸的能力有限，我们假设 血管内皮细胞对血浆的增加特别敏感 同型半胱氨酸，导致功能丧失。我们在这里所做的努力是 针对内皮细胞趋化因子表达的调控 低浓度的同型半胱氨酸。我们的具体目标是：1) 研究同型半胱氨酸循环形式的形成和稳定性。 这一目标是由以下假设驱动的：蛋白质结合的同型半胱氨酸， 循环中同型半胱氨酸的主要形式，可能在 动脉粥样硬化；2)研究血管中基因-营养的相互作用 细胞。这一目标是由这样的假设驱动的，即在血管细胞中， 依赖叶酸/B12的再甲基化是唯一可行的途径 同型半胱氨酸代谢，这个途径的效率是 取决于辅因子的可用性和酶的功能；以及3) 目的：研究同型半胱氨酸对血管细胞功能的影响。这一目标 是由这样一种假设驱动的，即由于能力有限 代谢同型半胱氨酸，血管功能可通过增加 在细胞内的同型半胱氨酸。这些研究将提供更好的 了解同型半胱氨酸在动脉粥样硬化形成中的作用 更有效的降低血浆总同型半胱氨酸的干预措施。

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease yet little is known about the vascular biochemistry and metabolism of homocysteine or the role it plays in atherogenesis. For the past three years our laboratory has focused on these problems. We have shown that vascular cells and tissues have a limited capacity to metabolize homocysteine. The catabolic transsulfuration pathway appears to be inoperative and the alternative remethylation pathway is not expressed. Thus, folate/B12-dependent remethylation may be the only pathway available in the vascular system for maintenance of low intracellular levels of homocysteine. We hypothesize that the overall efficiency of this pathway will be dependent upon cofactor availability and enzyme functionality. To test this hypothesis we have established a cellular model to explore gene-nutrient interactions. These studies will focus on methylenetetrahydrofolate reductase and methionine synthase, and enzymes that drive remethylation of homocysteine in vascular cells. Individuals who are homozygous for a common polymorphism (15 percent prevalence in many populations) of the reductase gene appear to have significantly higher total plasma homocysteine levels if coupled to low folate status. Because of their limited capacity to metabolize homocysteine, we hypothesize that endothelial cells are particularly sensitive to increases in plasma homocysteine, resulting in loss of function. Our efforts here are directed at the modulation of chemokine expression in endothelial cells by low concentrations of homocysteine. Our specific aims are: 1) to study the formation and stability of circulating forms of homocysteine. This aim is driven by the hypothesis that protein-bound homocysteine, the major form of homocysteine in circulation, may play a role in atherosclerosis; 2) to study gene-nutrient interactions in a vascular cells. This aim is driven by the hypothesis that, in vascular cells, folate/B12 dependent remethylation is the only pathway available for homocysteine metabolism and that the efficiency of this pathway is dependent upon cofactor availability and enzyme functionality; and 3) to study the effect of homocysteine on vascular cell function. This aim is driven by the hypothesis that, due to limited a capacity to metabolize homocysteine, vascular function can be altered by increases in intracellular homocysteine. These studies will provide a better understanding of the role of homocysteine in atherogenesis and perhaps more efficacious interventions to lower total plasma homocysteine.