SMALL, DENSE LDL IN THE PATHOGENESIS OF PREECLAMPSIA

小而密的 LDL 在先兆子痫发病机制中的作用

• 批准号: 2472530
• 负责人: Carl A Hubel
• 金额: $ 6.8万
• 依托单位: MAGEE-WOMEN'S HOSPITAL OF UPMC
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2472530
• 关键词: bioassay; blood chemistry; cardiovascular function; clinical research; density gradient ultracentrifugation; female; gestational age; human pregnant subject; hypertriglyceridemia; hyperuricemia; lipid metabolism; longitudinal human study; low density lipoprotein; oxidation; pathologic process; postpartum; preeclampsia; pregnancy; triglycerides; women's health

Preeclampsia is the leading cause of maternal death and increases perinatal mortality five-fold. Although the mechanisms underlying preeclampsia remain a mystery, compelling evidence indicates that dysfunction of the vascular endothelium is central to the disorder. The long term goal of the proposed research is to understand how alterations in lipid metabolism contribute to adverse changes in vascular function in preeclampsia. Clinically evident preeclampsia is preceded by marked hypertriglyceridemia. Metabolic changes producing elevated triglycerides can also shift the low-density lipoprotein (LDL) subfraction spectrum toward predominance of smaller, denser LDL. Small dense LDL has several altered physical properties capable of promoting endothelial cell dysfunction, including increased susceptibility to oxidative modification. Preliminary Data presented in this proposal demonstrates that a shift toward smaller, denser LDL occurs in preeclampsia relative to normal pregnancy. The hypothesis to be tested is that small dense LDL subspecies with increased oxidation susceptibility are present in greater absolute quantity and greater proportion in preeclampsia, and that these changes antedate clinically evident illness and resolve post partum. The strategy is to perform a longitudinal, nested case control study of particle diameter and oxidation susceptibility of LDL from nulliparous preeclamptics and gestationally matched controls. Thus, Aim 1 is to profile LDL particle size subclasses during gestation and 6 weeks post partum. Density gradient centrifugation is used to isolate LDL from plasma. Gradient gel electrophoresis is used to determine the predominant particle diameter in each sample. LDL is resubjected to density centrifugation to separate 6 distinct LDL subfractions. LDL mass in each subfraction is measured and the peak particle diameter of the predominant (by mass) subfraction is determined. Aim 2 is to analyze the oxidation kinetics of unfractionated LDL and predominant LDL subfractions during exposure of the isolated LDL to free radicals generated in vitro. At the conclusion of these experiments we will know whether preeclampsia is associated with a shift in LDL subclass patterns toward predominance of smaller, denser and more oxidation susceptible LDL. We will know if these changes are likely to be involved in pathogenesis (if increased before evident disease and resolved postpartum). The study will comprise a foundation for future research on adverse effects of abnormal LDL in preeclampsia.

先兆子痫是产妇死亡的主要原因， 围产期死亡率五倍。尽管潜在的机制 先兆子痫仍然是一个谜，令人信服的证据表明， 血管内皮的功能障碍是该疾病的核心。的 拟议研究的长期目标是了解如何改变 在脂质代谢中导致血管功能的不利变化 先兆子痫临床上明显的先兆子痫之前， 高胆固醇血症代谢变化导致甘油三酯升高 也可以改变低密度脂蛋白（LDL）亚组分谱 更小、更致密的LDL占优势。 小而密的LDL有几个 改变的物理性质能够促进内皮细胞 功能障碍，包括对氧化应激的敏感性增加 改性 本提案中提供的初步数据表明， 先兆子痫患者的低密度脂蛋白更小，密度更高， 正常的怀孕。 要检验的假设是， 氧化敏感性增加的LDL亚种存在于 先兆子痫的绝对量和比例更大， 这些变化早于临床上明显的疾病， 分娩的时候。 策略是进行纵向、嵌套式病例对照 低密度脂蛋白粒径及氧化敏感性研究 未生育的先兆子痫患者和妊娠匹配的对照。因此，目标 1是在妊娠期间描绘LDL颗粒大小亚类， 产后几周。密度梯度离心用于分离 血浆LDL梯度凝胶电泳用于测定 每个样品中的主要粒径。LDL重新受到 密度离心以分离6种不同的LDL亚组分。LDL质量 测量每个亚级分中的平均粒径， 确定主要（按质量计）亚组分。目的二是分析 未分级LDL和主要LDL的氧化动力学 亚组分在暴露过程中的分离LDL的自由基 在体外产生。在这些实验结束时，我们将知道 先兆子痫是否与LDL亚类模式的转变有关 朝着更小、更致密、更容易氧化的方向发展 低密度脂蛋白 我们将知道这些变化是否可能涉及 发病机制（如果在明显疾病之前增加并消退 产后）。这项研究将为今后的研究奠定基础 异常低密度脂蛋白对先兆子痫的副作用。