MODIFIED-LDL REGULATES MACROPHAGE PLASMINOGEN ACTIVATION

单核细胞从循环向内皮下的迁移 位置，以及它们随后转化为富含胆固醇的酯 泡沫细胞是病变中最早可识别的过程之一 队形。由于巨噬细胞是多能效应细胞，因此改变 在它们的功能中，作为脂质积累的结果 关于血管生物学的重要影响。在这方面， 巨噬细胞具有清道夫受体，介导低密度脂蛋白的摄取 在体外或体内进行修饰。初步研究表明， 清道夫受体配体刺激巨噬细胞分泌 纤溶酶原激活剂。巨噬细胞介导的纤溶酶原转化为 广谱蛋白水解酶纤溶酶已被证明发挥作用 炎症部位的组织破坏、组织重塑和细胞 有动静。此外，纤溶酶还可以改变血管的生物学特性。 其他水解酶、生长因子和激素。在内皮下层 与流体相不同，在太空中，纤溶酶可以结合细胞外基质 使其对循环抑制剂不敏感的成分或细胞。 因此，巨噬细胞对纤溶酶原的激活可能影响 血管内膜的结构完整性导致病灶消失。 内皮细胞及其后遗症。因此，我们将调查 修饰低密度脂蛋白对巨噬细胞依赖的纤溶酶原激活的调节 以全面和系统的方式。可溶性和膜缔合 纤溶酶原激活物(PA)和PA抑制物(PAL)活性将 评估和表征。我们将研究脂蛋白是如何调节的 PA和PAL的合成和分泌以及PA和PAL的表达 PAL基因的表达。我们将评估巨噬细胞对胶原蛋白和 非胶原基质成分，包括硫酸肝素蛋白多糖。 膜和可溶性PA在这些过程中的作用将是 调查过了。最后，我们将确定 巨噬细胞影响其对脂蛋白攻击的反应。为了这些 目的：我们将研究巨噬细胞群体的脂蛋白代谢。 用诱导剂和激活剂在体内诱导，细胞暴露在 在体外定义了细胞因子。然后我们将研究脂蛋白的调节。 这些受刺激的细胞表达PA和PAL。加在一起，这些 实验将提供对规则的全面分析 修饰低密度脂蛋白激活巨噬细胞纤溶酶原。

The emigration of monocytes from the circulation to a subendothelial position, and their subsequent transformation into cholesteryl ester rich foam cells is one of the earliest recognizable processes in lesion formation. Since macrophages are pluripotent effector-cells, alterations in their function as a consequence of lipid accumulation would have important ramifications regarding vascular biology. In this regard, macrophages possess a scavenger receptor which mediates the uptake of LDL modified in vitro or in vivo. Preliminary studies have demonstrated that ligands of the scavenger receptor stimulate macrophage secretion of plasminogen activator. Macrophage mediated conversion of plasminogen to the broad spectrum protease plasmin has been demonstrated to play a role in tissue destruction at inflammatory loci, tissue remodeling and cell movement. Furthermore, plasmin can alter the biological properties of other hydrolases, growth factors and hormones. In the subendothelial space, unlike in the fluid phase, plasmin can bind extracellular matrix components or cells rendering it insensitive to circulating inhibitors. Consequently, the activation of plasminogen by macrophages could affect the structural integrity of the intima leading to the focal loss of endothelial cells and its sequelae. Therefore, we will investigate the regulation of macrophage-dependent plasminogen activation by modified-LDL in a comprehensive and systematic manner. Soluble and membrane associated plasminogen activator (PA) and PA inhibitor (PAl) activities will be assessed and characterized. We will investigate how lipoprotein modulates the synthesis and secretion of PA and PAl, and the expression of PA and PAl mRNA. We will evaluate macrophage degradation of collagenous and noncollagenous matrix components, including heparin sulfate proteoglycan. The role of membrane and soluble PA in these processes will be investigated. Finally, we will determine how functional status of the macrophage influences their response to lipoprotein challenge. For these purposes, we will study lipo-protein metabolism by macrophage populations induced in vivo with eliciting and activating agents, and cells exposed to defined cytokines in vitro. We will then examine lipo-protein modulation of PA and PAl expression by these stimulated cells. Together, these experiments will provide a comprehensive analysis of the regulation of macrophage plasminogen activation by modified-LDL.