C-Reactive Protein And Atherosclerosis

描述(申请人提供)：C反应蛋白(CRP)是炎症的典型标记物。在健康志愿者中进行的大量研究已经证实，CRP可以预测心血管事件，是一种危险标记。最近的研究也支持C反应蛋白在动脉粥样硬化形成中的作用。C反应蛋白可诱导内皮细胞产生细胞黏附分子、趋化因子和内皮素-1，而单核细胞则产生活性氧、细胞因子和组织因子。我们最近发现，CRP直接抑制人主动脉内皮细胞内皮型一氧化氮合酶(ENOS)的表达和生物活性，并增强单核细胞与内皮细胞的黏附。此外，我们还发现，CRP抑制人主动脉内皮细胞释放前列环素，刺激PAL-1的释放。因此，这一建议的中心假设是，CRP通过对内皮细胞和单核细胞的作用促进动脉粥样硬化血栓形成。在特定的目标1中，我们将研究CRP降低人主动脉和冠状动脉内皮细胞eNOS表达和活性的机制。在特定的目标2，我们将测试在静态和定义的剪切流条件下，C反应蛋白对单核细胞内皮细胞黏附的影响，并将描绘涉及的分子机制。在特定的目标3中，我们将确定CRP的处理是否由受体介导，以及这是否解释了其生物学效应。最后，在特定的目标4中，我们将使用Spraogue-Dawley和Zucker大鼠在体内验证我们的发现。我们将在体内测试CRP对内皮血管反应性、低密度脂蛋白滞留和巨噬细胞生物学包括细胞黏附分子表达、组织因子、基质金属蛋白酶和泡沫细胞形成的影响。因此，这些研究将清楚地为我们提供进一步的科学证据，支持CRP在动脉粥样硬化血栓形成中的作用。

DESCRIPTION (provided by applicant): C-reactive protein (CRP) is the prototypic marker of inflammation. Numerous studies in healthy volunteers have confirmed that CRP predicts cardiovascular events and is a risk marker. Also recent studies support a role for CRP in atherogenesis. CRP has been shown to induce cell adhesion molecules, chemokines and endothelin-1 in endothelial cells (EC) and reactive oxygen species, cytokines and tissue factor in monocytes. We have recently shown that CRP directly inhibits the expression and bioactivity of endothelial nitric-oxide synthase (eNOS) in human aortic endothelial cells and augments monocyte-endothelial cell adhesion. Furthermore we have also shown that CRP inhibits prostacyclin release and stimulates PAl-1 release from human aortic EC. Thus the central hypothesis of this proposal is that CRP promotes atherothrombosis via effects on both endothelial cells and monocytes. In Specific Aim 1 we will examine the mechanisms via which CRP decreases eNOS expression and activity in human aortic and coronary artery endothelial cells. In Specific Aim 2, we will test the effect of CRP on monocyte endothelial cell adhesion under both static and defined shear flow conditions and will delineate the molecular mechanisms involved. In Specific Aim 3 we will determine if the processing of CRP is receptor mediated and if this accounts for its biological effects. Finally in Specific Aim 4, we will use Sprague-Dawley and Zucker rats to confirm our findings in vivo. We will test the effect of CRP in vivo on endothelial vasoreactivity, on low density lipoprotein retention and on macrophage biology including cellular adhesion molecule expression, secretion of tissue factor, matrix metalloproteinases and foam cell formation. Thus, these studies will clearly provide us with further scientific evidence in support of the role of CRP in atherothrombosis.