MODIFIED-LDL REGULATES MACROPHAGE PLASMINOGEN ACTIVATION

单核细胞从循环中迁移到内皮下 位置，以及它们随后转化为富含胆固醇酯的 泡沫细胞是最早发现的病变过程之一 阵由于巨噬细胞是多能效应细胞， 在它们的功能中，由于脂质积累， 血管生物学的重要分支。在这方面，委员会注意到， 巨噬细胞具有介导LDL摄取的清道夫受体 在体外或体内修饰。 初步研究表明， 清道夫受体的配体刺激巨噬细胞分泌 纤溶酶原激活物。 巨噬细胞介导的纤溶酶原向 已经证明广谱蛋白酶纤溶酶在 在炎症部位组织破坏、组织重塑和细胞 运动 此外，纤溶酶可以改变细胞的生物学特性， 其他水解酶、生长因子和激素。 在内皮下 与在液相中不同，纤溶酶可以结合细胞外基质 使其对循环抑制剂不敏感的组分或细胞。 因此，巨噬细胞对纤溶酶原的激活可以影响 内膜的结构完整性导致局部丧失 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性纤溶酶原激活的调节 以全面和系统的方式。 可溶性和膜结合 纤溶酶原激活剂（PA）和PA抑制剂（PA1）活性将被测定。 评估和表征。 我们将研究脂蛋白如何调节 PA和PAI的合成和分泌，以及PA和PAI的表达， PAI mRNA。 我们将评估巨噬细胞降解胶原和 非胶原基质成分，包括硫酸肝素蛋白聚糖。 膜和可溶性PA在这些过程中的作用将是 研究了 最后，我们将确定 巨噬细胞影响其对脂蛋白攻击的反应。为这些 目的：研究巨噬细胞群的脂蛋白代谢 用引发剂和活化剂在体内诱导，以及暴露于 定义的细胞因子。 然后我们将研究脂蛋白调节 PA和PAI的表达。 所有这些 实验将提供一个全面的分析， 巨噬细胞纤溶酶原激活的修饰LDL。

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.