Pregnancy, Pre-eclampsia, Anti-oxidants and Endothelial Cell Function

妊娠、先兆子痫、抗氧化剂和内皮细胞功能

• 批准号: 7896757
• 负责人: GAUTAM CHAUDHURI
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896757
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adhesions; Affect; African American; Antioxidants; Apoptosis; Apoptotic; Ascorbic Acid; Attenuated; Biological Models; Cell Adhesion Molecules; Cell Nucleus; Cell Survival; Cell physiology; Cells; Clinical Research; Cycloheximide; Cytoplasm; Cytosol; Data; Disease; Down-Regulation; Eclampsia; Effectiveness; Endothelial Cells; Estrogens; Etiology; Exposure to; Extravasation; Fetus; Foundations; Functional disorder; Human; Hypertension; Inhibition of Apoptosis; Lead; Leukocytes; Literature; MAPK11 gene; MAPK14 gene; Mediating; Messenger RNA; Mitochondria; Mothers; National Institute of Child Health and Human Development; Oxidative Stress; Pathogenesis; Pathway interactions; Phosphorylation; Placenta; Pre-Eclampsia; Pregnancy; Prevention; Principal Investigator; Prophylactic treatment; Prostaglandins I; Proteins; Research Personnel; Risk; Role; Secondary to; Signal Pathway; Signal Transduction; Swelling; Symptoms; Testing; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Umbilical vein; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vitamin E; Vitamins; Woman; atherogenesis; exposed human population; fetal; interest; mRNA Expression; migration; monocyte; prevent; programs; prophylactic; research study; socioeconomics

DESCRIPTION (provided by applicant): A current hypothesis for the etiology of pre-eclampsia is that endothelial dysfunction is secondary to oxidative stress and some clinical studies have indicated that prophylactic administration of anti-oxidants may be useful in its prevention. A much larger trial utilizing the anti-oxidants vitamin C and vitamin E is, at present, being carried out by the Maternal-Fetal Network of the NICHD to assess their effectiveness in the prevention of pre-eclampsia. Endothelial cell activation is usually a constant accompaniment with this condition. Endothelial cell activation leads to endothelial cell dysfunction and is also accompanied by expression of adhesion molecules, i.e. vascular cell adhesion molecule-1 (VCAM-1), and other adhesion molecules. This leads to adhesion of monocytes to endothelial cells resembling early atherogenesis. There is evidence in the literature that tumor necrosis factor a (TNFa) may be released by the placenta and activated leukocytes leading to activation of endothelial cells. The current proposal will mainly focus on mechanisms by which estrogens and anti-oxidants prevent TNFa-induced endothelial cell activation and apoptosis. We will, therefore, test the following four hypotheses. Hypothesis 1: Exposure of endothelial cells to TNFa leads, initially, to activation of the cells leading to VCAM-1 expression and increased synthesis of anti-apoptotic proteins, followed by stimulation of the survival pathway. Hypothesis 2: Estrogen and its metabolites prevent TNFa-induced activation, as well as apoptosis of HUVEC, by increasing the expression of eNOS and phosphorylation of Akt and ERK 1/2, in spite of the absence of migration of NFkB to the nucleus, thereby, directing the cells to the "survival pathway". Hypothesis 3: Anti-oxidants prevent endothelial cell activation and inhibit NFkB migration to the nucleus following exposure of endothelial cells to TNFa by an NO-independent Fak-mediated mechanism. Hypothesis 4: Anti-oxidants attenuate apoptosis in endothelial cells exposed to TNFa by upregulation of ERK 1/2 phosphorylation and downregulation of p38 phosphorylation. Results from these studies will also help explain the different mechanism(s) by which estrogens and anti-oxidants prevent activation of endothelial cells and apoptosis and, thereby, lay the scientific foundation by which anti-oxidants administered to women may prevent pre- eclampsia in women at risk of developing this condition. Pre-eclampsia is a condition that suddenly develops during pregnancy and is accompanied by high blood pressure, swelling of the body, and leakage of proteins. This condition can adversely affect both the mother and the fetus. Pre-eclampsia is more prevalent in Afro-Americans and is also seen in the lower socio-economic groups. Results from our studies will indicate to us which anti-oxidants are likely to be more effective than others and which can be used clinically to prevent this condition.

描述（由申请人提供）：目前关于先兆子痫病因的假设是内皮功能障碍继发于氧化应激，一些临床研究表明，预防性给予抗氧化剂可能有助于预防其发生。目前，NICHD的母胎网络正在进行一项更大规模的试验，利用抗氧化剂维生素C和维生素E来评估它们在预防先兆子痫方面的有效性。内皮细胞活化通常伴随此病。内皮细胞活化导致内皮细胞功能障碍，同时伴有粘附分子的表达，即血管细胞粘附分子-1 （VCAM-1）等粘附分子的表达。这导致单核细胞粘附到内皮细胞，类似于早期动脉粥样硬化。文献证据表明，肿瘤坏死因子a （tumor necrosis factor a, TNFa）可能由胎盘释放，激活白细胞，导致内皮细胞活化。目前的建议将主要集中于雌激素和抗氧化剂阻止tnf诱导的内皮细胞活化和凋亡的机制。因此，我们将检验以下四个假设。假设1：内皮细胞暴露于TNFa，最初导致细胞活化，导致VCAM-1表达和抗凋亡蛋白合成增加，随后刺激存活途径。假设2：雌激素及其代谢物通过增加eNOS的表达以及Akt和ERK 1/2的磷酸化来阻止tnfa诱导的HUVEC活化和凋亡，尽管NFkB没有向细胞核迁移，从而引导细胞进入“生存途径”。假设3：抗氧化剂通过no独立的fak介导机制，阻止内皮细胞暴露于TNFa后的内皮细胞活化并抑制NFkB向细胞核的迁移。假设4：抗氧化剂通过上调ERK 1/2磷酸化和下调p38磷酸化来减轻暴露于tnf fa的内皮细胞的凋亡。这些研究的结果也将有助于解释雌激素和抗氧化剂预防内皮细胞活化和细胞凋亡的不同机制，从而为女性抗氧化剂预防有子痫前期风险的女性子痫前期奠定科学基础。先兆子痫是一种在怀孕期间突然出现的疾病，并伴有高血压、身体肿胀和蛋白质渗漏。这种情况会对母亲和胎儿产生不利影响。先兆子痫在非裔美国人中更为普遍，也见于社会经济地位较低的群体。我们的研究结果将告诉我们，哪些抗氧化剂可能比其他抗氧化剂更有效，哪些抗氧化剂可以在临床上用于预防这种情况。