ATHEROGENICITY OF POSTPRANDIAL TRIGLYCRIDE-RICH LIPOPROTEINS (PPTGRLP)

餐后脂蛋白代谢紊乱被认为是一种 动脉粥样硬化早期和血栓形成的致病因素 冠心病(CAD)的并发症。这项提议的一个目标 是定义特定的启动机制，通过这些机制异常 餐后脂蛋白代谢参与动脉粥样硬化的形成 和血栓形成。关键的早期事件涉及到 循环单核细胞和内皮细胞：单核细胞增多 附着于内皮细胞，这是形成脂肪条纹的先兆，以及 组织因子(TF)表达增强，先于血栓 队形。触发机制尚不清楚，但提供的数据 这里和文献中都表明单核细胞的脂质变化和 ECS与单核细胞黏附增强和转铁蛋白增加有关 两种类型的细胞都有活性。一个潜在的每日扰动，它有 在单核细胞和内皮细胞功能方面缺乏关注，是异常的pp 冠心病风险增加的受试者的脂蛋白代谢。两者都有 单核细胞和内皮细胞直接暴露于血液和ppTGRLPs。在……里面 换句话说，我们认为瞬时的ppTGRLP可能有助于 动脉粥样硬化形成和血栓形成而不进入动脉壁， 这一过程有时被认为不太可能用于大型TGRLP。的确， 初步研究表明，从中国分离的循环单核细胞 在规定的高脂肪饮食后4小时有风险的受试者增加了 胆固醇和甘油三酯含量增加，与内皮细胞的粘附性增加，转铁蛋白增加 活动。因此，我们建议测试增强的假设 异常的ppTGRLP通过MBP与单核细胞和内皮细胞整合 200/235受体导致(1)粘附性增加，这是由于 细胞表面整合素(VLA-4和LFA-1)的活性或表达 单核细胞及其受体(CAM-1、ICAM-1或E-选择素) ECs，以及(2)单核细胞和ECs的促凝血活性增加， 由于组织因子(Tf)的诱导或激活。鲜为人知 PP脂蛋白代谢对单核细胞-内皮细胞黏附的影响 Tf表达和参与ppTGRLP摄取的受体。这 建议书直接解决了这些差距，并应提供基本的蜂窝 和分子机制来解释某些疾病增加的冠心病风险 空腹脂蛋白谱异常和异常的受试者 餐后反应。

Perturbed postprandial lipoprotine metabolism is considered a contributing factor in premature atherosclerosis and the thrombotic complications of coronary artery disease (CAD). A goal of this proposal is to define specific initiating mechanisms by which abnormal postprandial (pp) lipoprotein metabolism contributes to atherogenesis and thrombosis. Key early events involve functional changes in circulating monocytes and endothelial cells (ECs): increased monocyte adherence to ECs, which precedes formation of fatty streaks, and enhanced expression of tissue factor (TF), which precedes clot formation. Triggering mechanisms are not yet known,but data presented here and in the literature suggest that lipid changes in monocytes and ECs are associated with enhanced monocyte adherence and increased TF activity in both cell types. A potential daily perturbant, which has lacked attention in terms of monocyte and EC function, is abnormal pp lipoprotein metabolism in subjects at increased CAD risk. Both monocytes and ECs are directly exposed to blood and to ppTGRLPs. In other words, we suggest that transient ppTGRLPs may contribute to atherogenesis and thrombosis without entering the arterial wall, a process sometimes considered unlikely for large TGRLP. Indeed, preliminary studies show that circulating monocytes isolated from subjects at risk 4 hours after a defined high-fat meal have increased cholesterol and TG content, increased adhesion to ECs, and increased TF activity. We therefore propose to test the hypothesis that enhanced integration of abnormal ppTGRLP with monocytes and ECs via the MBP 200/235 receptor leads to (1) increased adhesion, due to modulation of activity or expression of cell surface integrins (VLA-4 and LFA-1) on monocytes and their counter receptors (CAM-1, ICAM--1 or E-selectin) on ECs, and (2) increased procoagulant activity in both monocytes and ECs, due to induction or activation of tissue factor (TF). Little is known about the effects of pp lipoprotein metabolism on monocyte-EC adhesion and TF expression and the receptor responsible for ppTGRLP uptake. This proposal directly addresses these gaps and should provide basic cellular and molecular mechanisms to explain the increased CAD risk of certain subjects with abnormal fasting lipoprotein profiles and abnormal postprandial responses.