C-Reactive Protein And Atherosclerosis

C反应蛋白和动脉粥样硬化

• 批准号: 6823152
• 负责人: Ishwarlal Jialal
• 金额: $ 36.78万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823152
• 关键词: SDS polyacrylamide gel electrophoresis; acute phase protein; atherosclerosis; cell adhesion; endothelin; enzyme activity; flow cytometry; gel mobility shift assay; hemodynamics; laboratory rat; low density lipoprotein; metalloendopeptidases; monocyte; nitric oxide synthase; phosphorylation; polymerase chain reaction; shear stress; tissue /cell culture; vasomotion; western blottings

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.

描述（由申请人提供）：C反应蛋白（CRP）是炎症的原型标志物。对健康志愿者的大量研究证实，CRP 可以预测心血管事件，并且是一个风险标记。最近的研究也支持 CRP 在动脉粥样硬化形成中的作用。 CRP 已被证明可诱导内皮细胞 (EC) 中的细胞粘附分子、趋化因子和内皮素-1，以及单核细胞中的活性氧、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中内皮一氧化氮合酶 (eNOS) 的表达和生物活性，并增强单核细胞与内皮细胞的粘附。此外，我们还表明CRP抑制前列环素释放并刺激人主动脉EC释放PAl-1。因此，该提议的中心假设是，CRP 通过对内皮细胞和单核细胞的影响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中 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。我们将测试体内 CRP 对内皮血管反应性、低密度脂蛋白保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。