LIPOPROTEIN LIPASE AND PREECLAMPSIA

先兆子痫是产妇死亡的主要原因，使围产期死亡率增加5倍。有令人信服的证据表明，母体内皮功能障碍有助于子痫前期的发病机制。高甘油三酯血症、高密度脂蛋白（HDL）胆固醇降低和异常小尺寸低密度脂蛋白（LDL）颗粒是子痫前期的特征。我们提出这些脂质异常通过氧化应激的产生促进子痫前期内皮功能障碍。脂蛋白脂肪酶（LPL）在清除循环中的甘油三酯中起着至关重要的作用。LPL缺陷在心血管疾病发展中的重要性日益被认识。LPL基因的几种常见变异促进甘油三酯增加、高密度脂蛋白胆固醇降低和小密度脂蛋白胆固醇的三联体。这些功能变异对血脂异常的影响在怀孕时更加突出。在我们的高加索人群中，总共有18.8%的先兆子痫患者是LPL基因的N291S或D9N编码序列变异的杂合，而正常妊娠对照组的这一比例为4.6%。因此，目的1是检验这些观察结果是否可以推广到其他人群。我们将比较LPL基因四种最常见的功能性变异在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的流行程度。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，然后在病例和对照中进行基因分型。我们假设LPL基因的变异对血脂异常的易感性在子痫前期的女性中被过度代表。目的3是比较按基因型分层的子痫前期妇女的血浆脂质、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，那些携带酶活性降低的LPL变异的女性将表现出特别不利的血液特征。在Aim 4中，我们将测量产后12周妇女血浆LPL酶活性，以进一步验证LPL体质缺乏（激素和/或遗传介导）与子痫前期相关的假设。在Aim 5中，我们将使用LPL敲除小鼠，探讨杂合LPL缺乏对妊娠期间血管功能内皮调节的影响。这种系统的方法将有助于阐明血脂异常与子痫前期发病机制之间的联系，并可能为预防或治疗这种疾病提供线索。

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.