Homocysteine: Vascular Biochemistry and Metabolism

高同型半胱氨酸血症是心血管疾病的一个强烈的独立危险因素，也是阿尔茨海默病的一个新的危险因素。我们的工作主要集中在：1)同型半胱氨酸在血管细胞和组织中的代谢；2)同型半胱氨酸在循环中的生物化学；3)同型半胱氨酸在动脉粥样硬化形成和血管疾病进展中的致病机制。我们假设血管细胞对高同型半胱氨酸血症中升高的同型半胱氨酸水平特别脆弱，因为它们代谢同型半胱氨酸的能力有限。我们还认为，同型半胱氨酸的致病性不是由于它在循环中经历氧化时产生活性氧物种的能力，从而导致氧化应激。我们认为，同型半胱氨酸攻击特定的分子靶点，并对其生物活性进行不利的调节。我们称之为“分子靶标假说”，作为“氧化应激假说”的替代。这项工作的长期目标是：1)确定同型半胱氨酸的细胞内和细胞外分子靶点，并了解同型半胱氨酸如何相互作用和调节其活性，2)了解同型半胱氨酸靶向分子如何导致细胞功能障碍，以及3)利用这一知识，开发在疾病状态下降低tHcy的策略，如肾功能衰竭。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生物化学。这一目标是基于循环中所有形式的同型半胱氨酸在动脉粥样硬化形成和其他疾病过程中发挥重要作用的假设；2)研究同型半胱氨酸在血管细胞中的运输、代谢和基因-营养相互作用。3)研究同型半胱氨酸对血管内皮细胞和血管内皮细胞功能的影响；3)研究同型半胱氨酸对血管内皮细胞的作用。这一目标是由同型半胱氨酸通过靶向和调节细胞上和细胞内特定分子的活性来改变血管细胞功能的假设驱动的。

Hyperhomocysteinemia is a strong independent risk factor for cardiovascular disease and is an emerging risk factor for Alzheimer's disease. The focus of our work has been on: 1) homocysteine metabolism in human vascular cells and tissues, 2) biochemistry of homocysteine in the circulation, and 3) pathogenic mechanisms of homocysteine in atherogenesis and the progression of vascular disease. We hypothesized that vascular cells would be particularly vulnerable to the increased levels of homocysteine that occur in hyperhomocysteinemia because of their limited capacity to metabolize homocysteine. We also suggest that homocysteine pathogenicity is not due to its ability to generate reactive oxygen species, hence oxidative stress, when undergoing oxidation in the circulation. We believe that homocysteine attacks specific molecular targets and adversely modulates their biological activity. We call this the "molecular target hypothesis", which we offer as an alternative to the "oxidative stress hypothesis". The long-term objectives of this work are: 1) to identify intracellular and extracellular molecular targets of homocysteine and understand how homocysteine interacts and modulates their activity, 2) to learn how homocysteine-targeted molecules cause cellular dysfunction, and 3) with this knowledge, develop strategies to lower tHcy in disease states such as renal failure. Our specific aims are: 1) to study the formation and biochemistry of the circulating forms of homocysteine. This aim is driven by the hypothesis that all forms of homocysteine in circulation play important roles in atherogenesis and other disease processes, 2) to study homocysteine transport, metabolism and gene-nutrient interactions in vascular cells. This aim is driven by the hypothesis that folate/cobalamin-dependent remethylation is the only pathway available in vascular cells for homocysteine metabolism and that the efficiency of remethylation is dependent upon cofactor availability and enzyme functionality, and 3) to study the effect of homocysteine on endothelial and smooth muscle cell function. This aim is driven by the hypothesis that homocysteine alters vascular cell function by targeting and modulating the activity of specific molecules on and within the cell.