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 然而，对血管生物化学和 同型半胱氨酸代谢或其在动脉粥样硬化形成中的作用。 为 在过去的三年里，我们的实验室一直致力于解决这些问题。 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。 分解代谢转硫途径出现 而另一种再甲基化途径 表达。 因此，叶酸/B12依赖性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通路 细胞内同型半胱氨酸水平。 我们假设， 该途径的效率将取决于辅因子的可用性 和酶功能性。 为了验证这一假设，我们建立了 探索基因-营养相互作用的细胞模型。 这些研究 将重点研究亚甲基四氢叶酸还原酶和蛋氨酸 合成酶，以及驱动同型半胱氨酸再甲基化的酶， 血管细胞 对于一个共同的基因是纯合子的个体 多态性（在许多人群中的患病率为15%） 还原酶基因似乎有显着较高的总血浆 高半胱氨酸水平，如果再加上低叶酸状态。 因为他们的 有限的能力代谢同型半胱氨酸，我们假设， 内皮细胞对血浆中 同型半胱氨酸，导致功能丧失。 我们的努力是 针对内皮细胞中趋化因子表达的调节 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。 这一目标是由蛋白质结合的同型半胱氨酸， 同型半胱氨酸在循环中的主要形式，可能在 动脉粥样硬化; 2）研究血管中的基因-营养相互作用， 细胞 这一目标是由假设驱动的，在血管细胞中， 叶酸/B12依赖性再甲基化是唯一可用的途径， 同型半胱氨酸代谢，这一途径的效率是 取决于辅因子可用性和酶功能性;和3） 探讨同型半胱氨酸对血管细胞功能的影响。 这一目标 是由假设驱动的，由于能力有限， 代谢同型半胱氨酸，血管功能可以改变增加 细胞内同型半胱氨酸 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， 更有效的干预措施，以降低总血浆同型半胱氨酸。

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.