C-Reactive Protein And Atherosclerosis

描述（由申请方提供）：C反应蛋白（CRP）是炎症的原型标志物。在健康志愿者中进行的大量研究证实，CRP可预测心血管事件，是一种风险标志物。最近的研究也支持CRP在动脉粥样硬化形成中的作用。CRP可诱导内皮细胞产生细胞粘附分子、趋化因子和内皮素-1，诱导单核细胞产生活性氧、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一氧化氮合酶（eNOS）的表达和生物活性，并增强单核细胞-内皮细胞粘附。此外，我们还表明，CRP抑制前列环素释放和刺激PAI-1释放从人主动脉EC。因此，该建议的中心假设是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。在具体目标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。在具体目标2中，我们将在静态和确定的剪切流条件下测试CRP对单核细胞内皮细胞粘附的影响，并将描述所涉及的分子机制。在具体目标3中，我们将确定CRP的加工是否是受体介导的，以及这是否解释了其生物学效应。最后，在具体目标4中，我们将使用Sprague-Dawley和Zucker大鼠来证实我们的体内发现。我们将测试CRP在体内对内皮血管反应性、低密度脂蛋白滞留和巨噬细胞生物学（包括细胞粘附分子表达、组织因子分泌、基质金属蛋白酶和泡沫细胞形成）的影响。因此，这些研究将明确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.