LIPOPROTEIN LIPASE AND PREECLAMPSIA

脂蛋白脂肪酶和先兆子痫

• 批准号: 6039516
• 负责人: Carl A Hubel
• 金额: $ 24.57万
• 依托单位: MAGEE-WOMEN'S HOSPITAL OF UPMC
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6039516
• 关键词: clinical research; developmental genetics; enzyme activity; female; fibronectins; gene expression; genetic mapping; genetic susceptibility; high density lipoproteins; human pregnant subject; human subject; insulin; laboratory mouse; lipoprotein lipase; low density lipoprotein; malonaldehyde; preeclampsia; pregnancy disorder; triglycerides; vascular cell adhesion molecule; women's health

Preeclampsia is a leading cause of maternal death and increases perinatal death five-fold. There is compelling evidence that maternal endothelial dysfunction contributes to the pathogenesis of preeclampsia. Hypertriglyceridemia, decreases in high density lipoprotein (HDL) cholesterol, and abnormally small-sized low density lipoprotein (LDL) particles are characteristic features of preeclampsia. We have proposed that these lipid abnormalities promote endothelial dysfunction in preeclampsia through the generation of oxidative stress. Lipoprotein lipase (LPL) plays a vital role in the clearance of triglycerides from the circulation. The importance of LPL defects in the development of cardiovascular disease is increasingly recognized. Several common variations in the LPL gene promote the triad of increased triglyceride, decreased HDL cholesterol, and small-sized LDL. The dyslipidemic effects of these functional variants are accentuated by pregnancy. In our Caucasian population, a sum total of 18.8% of preeclamptics are heterozygous for either the N291S or D9N coding sequence variants of the LPL gene, compared with 4.6% of normal pregnancy controls. Accordingly, Aim 1 is to test whether these observations can be generalized to other populations. We will compare the prevalence of the four most common, functional variants in the LPL gene in Caucasians and African-Americans from western Pennsylvania, and in Icelandic women. Aim 2 is to sequence the coding and promoter regions of the LPL gene to identify other functional variants, which will then be genotyped in cases and controls. We posit that variations in the LPL gene the predispose to dyslipidemia are over-represented in women with preeclampsia. Aim 3 is to compare plasma lipids, lipid peroxidation products, and markers of endothelial dysfunction in women with preeclampsia stratified by genotype. We hypothesize that, among women with preeclampsia, those carrying LPL variants with reduced enzymatic activity will display an especially adverse blood profile. In Aim 4, we will measure plasma LPL enzyme activity in women 12 weeks postpartum to further test the hypothesis that a constitutional deficiency in LPL (hormonally and/or genetically mediated) is associated with preeclampsia. In Aim 5, we will explore the effects of heterozygous LPL deficiency on endothelial regulation of vascular function during pregnancy, using the LPL knockout mouse. This systematic approach will help to clarify the link between dyslipidemia and the pathogenesis of preeclampsia and could provide clues to prevention or treatment of the disorder.

先兆子痫是孕产妇死亡的主要原因，并使围产期死亡率增加五倍。有令人信服的证据表明母体内皮功能障碍导致先兆子痫的发病机制。高甘油三酯血症、高密度脂蛋白（HDL）胆固醇降低和异常小的低密度脂蛋白（LDL）颗粒是先兆子痫的特征。我们提出，这些脂质异常通过产生氧化应激而促进先兆子痫的内皮功能障碍。脂蛋白脂肪酶 (LPL) 在清除循环中的甘油三酯方面发挥着至关重要的作用。 LPL 缺陷在心血管疾病发展中的重要性日益得到认识。 LPL 基因中的几种常见变异会促进甘油三酯升高、高密度脂蛋白胆固醇降低和小尺寸低密度脂蛋白三联征。这些功能变异的血脂异常效应因怀孕而加剧。在我们的白种人群体中，总共 18.8% 的先兆子痫患者的 LPL 基因的 N291S 或 D9N 编码序列变异是杂合的，而正常妊娠对照的这一比例为 4.6%。因此，目标 1 是测试这些观察结果是否可以推广到其他人群。我们将比较来自宾夕法尼亚州西部的白种人和非裔美国人以及冰岛女性中 LPL 基因中四种最常见的功能性变异的患病率。目标 2 是对 LPL 基因的编码区和启动子区进行测序，以确定其他功能变异，然后对病例和对照进行基因分型。我们推测，在患有先兆子痫的女性中，易患血脂异常的 LPL 基因变异过多。目标 3 是比较按基因型分层的先兆子痫女性的血浆脂质、脂质过氧化产物和内皮功能障碍标志物。我们假设，在患有先兆子痫的女性中，携带酶活性降低的 LPL 变异的女性将表现出特别不利的血液特征。在目标 4 中，我们将测量产后 12 周女性的血浆 LPL 酶活性，以进一步检验 LPL 体质缺乏（激素和/或遗传介导的）与先兆子痫相关的假设。在目标 5 中，我们将使用 LPL 敲除小鼠探讨杂合 LPL 缺陷对妊娠期间血管功能内皮调节的影响。这种系统方法将有助于阐明血脂异常与先兆子痫发病机制之间的联系，并可为预防或治疗该疾病提供线索。