MECHANISM(S) OF EXCESS LDL OXIDATION IN DIABETES

糖尿病是一种常见的疾病，与临床显著相关。 后遗症，包括动脉粥样硬化。多达四分之三的人 糖尿病患者的死亡是由于冠心病和 冠心病的危险因素在糖尿病患者中尤其普遍。 尽管有这样的观察，流行病学数据表明 动脉粥样硬化的传统危险因素只解释了25% 糖尿病中过量的CHD。这个项目是基于 假设糖尿病中冠心病发病率的增加是由于， 部分是由于加速了低密度致动脉粥样硬化的修饰 通过氧化产生脂蛋白(LDL)。这个项目的目标是， 因此，确定高密度脂蛋白的作用机制(S) 糖尿病中的氧化作用。 我们将通过研究在低密度脂蛋白中的作用来实现这一目标 糖尿病的两个主要特征--高血糖和氧化 血脂异常。我们将首先描述一下葡萄糖的作用(S) 在低密度脂蛋白颗粒上，可能会损害其抗氧化能力。 将研究三种不同的低密度脂蛋白氧化系统： 金属离子(Cu2+，Fe3+)，含水过氧自由基，培养 血管细胞，以深入了解其机制(S) 对葡萄糖的影响负责。机制(S)将确定 通过测量葡萄糖对金属离子结合和的影响 低密度脂蛋白的还原，并评估预制脂的作用 低密度脂蛋白中的过氧化氢和特定的活性氧 氧化。接下来我们将确定已知的葡萄糖介导型 对血管细胞代谢的影响导致细胞功能增强 低密度脂蛋白氧化。葡萄糖对细胞能力的影响 修饰低密度脂蛋白将通过探索相关机制来表征 (即细胞产生超氧化物、一氧化氮[NO]、 还原的硫醇和过渡金属离子的细胞还原) 以及所涉及的信令过程。由于维管细胞 部分由氧化低密度脂蛋白(ox-LDL)引起的功能障碍也是 在动脉粥样硬化的病理生理学方面，我们将 描述葡萄糖对特定细胞反应的影响 对氧化型低密度脂蛋白，包括内皮细胞、单核细胞、一氧化氮的产生 黏附和巨噬细胞摄取氧化低密度脂蛋白。在最终的目标中 这个项目，我们将调查与糖尿病相关的影响 血脂异常对低密度脂蛋白氧化的影响。具体来说，我们将测定低密度脂蛋白 与糖尿病相关的成分变化 血脂异常，并将这些变化与低密度脂蛋白氧化抵抗有关。 这些实验的相关发现将用以下方法建模 重组低密度脂蛋白以确定分子机制。在这 方式，我们期待确定的确切机制(S) 糖尿病患者体内过多的低密度脂蛋白氧化，这可能导致新的 糖尿病血管疾病的治疗。

Diabetes is a common disorder associated with significant clinical sequelae, including atherosclerosis. Up to three-fourths of all deaths among diabetics are due to coronary heart disease (CHD) and risk factors for CHD are particularly prevalent in diabetics. Despite this observation, epidemiologic data suggest that traditional risk factors for atherosclerosis explain only 25% of the excess CHD in diabetes. This project is based on the hypothesis that the increased incidence of CHD in diabetes is due, in part, to accelerated atherogenic modification of low-density lipoprotein (LDL) by oxidation. The objective of this project, therefore, is to determine the mechanism(s) of excess LDL oxidation in diabetes. We will pursue this objective by examining the role in LDL oxidation of two cardinal features of diabetes, hyperglycemia and dyslipidemia. We will first characterize the effect(s) of glucose on the LDL particle that may impair its resistance to oxidation. Three different systems of LDL oxidation will be investigated: metal ions (Cu2+, Fe3+), aqueous peroxyl radicals, and cultured vascular cells in order to gain insight into the mechanism(s) responsible for a glucose effect. Mechanism(s) will be identified by measuring the effects of glucose on metal ion binding to and reduction by LDL, and assessing the role of preformed lipid hydroperoxides and specific reactive oxygen species in LDL oxidation. We will next determine if known glucose-mediated effects on vascular cell metabolism result in enhanced cellular LDL oxidation. Effects of glucose on the cellular capacity to modify LDL will be characterized by exploring relevant mechanisms (i.e., cellular production of superoxide, nitric oxide [NO], reduced thiol, and cellular reduction of transition metal ions) and the signaling processes involved. Since vascular cell dysfunction caused, in part, by oxidized LDL (ox-LDL) is also important in the pathophysiology of atherosclerosis, we will characterize the effect of glucose on specific cellular responses to ox-LDL, including endothelial cell NO production and, monocyte adhesion, and macrophage uptake of ox-LDL. In the final aim of this project, we will investigate the effects of diabetes-related dyslipidemia on LDL oxidation. Specifically, we will determine LDL compositional changes that are associated with diabetic dyslipidemia and relate these changes to LDL oxidative resistance. Relevant findings from these experiments will be modeled using reconstituted LDL to identify molecular mechanisms. In this manner, we anticipate identifying the precise mechanism(s) of excess LDL oxidation in diabetes, which may result in novel treatments for diabetic vascular disease.