C-Reactive Protein And Atherosclerosis

C反应蛋白和动脉粥样硬化

• 批准号: 7232413
• 负责人: Ishwarlal Jialal
• 金额: $ 33.73万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7232413
• 关键词: Accounting; Arterial Fatty Streak; Atherosclerosis; Biological; Biology; Blood Vessels; C-reactive protein; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Complement; Condition; Coronary artery; Endothelial Cells; Endothelin-1; Epoprostenol; Event; Foam Cells; Human; Inflammation; Localized; Low-Density Lipoproteins; Matrix Metalloproteinases; Mediating; Molecular; Play; Process; Prostaglandins I; Protein C; Reactive Oxygen Species; Risk Marker; Role; Smooth Muscle Myocytes; System; Testing; Thromboplastin; Zucker Rats; atherogenesis; atherothrombosis; chemokine; cytokine; healthy volunteer; human NOS3 protein; in vivo; macrophage; monocyte; receptor

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）是炎症的原型标记。在健康志愿者中进行的大量研究证实，CRP预测心血管事件，并且是风险标志。最近的研究还支持CRP在动脉粥样硬化中的作用。已显示CRP在单核细胞中诱导内皮细胞（EC）和活性氧，细胞因子和组织因子中的细胞粘附分子，趋化因子和内皮素-1。我们最近表明，CRP直接抑制人主动脉内皮细胞中内皮硝酸合酶（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抑制前列环蛋白的释放并刺激PAL-1从人主动脉EC中释放。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。在特定目标1中，我们将检查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。在特定的目标2中，我们将测试CRP对静态和定义的剪切流条件下单核细胞内皮细胞粘附的影响，并描述所涉及的分子机制。在特定的目标3中，我们将确定CRP的处理是否是受体介导的，以及这是否解释了其生物学作用。最后，在特定的目标4中，我们将使用Sprague-Dawley和Zucker大鼠在体内确认我们的发现。我们将测试CRP体内对内皮血管反应性，低密度脂蛋白保留和巨噬细胞生物学的影响，包括细胞粘附分子表达，组织因子的分泌，基质金属蛋白酶和泡沫细胞形成。因此，这些研究清楚地将为我们提供进一步的科学证据，以支持CRP在动脉粥样硬化中的作用。