Proatherogenic properties of platelet factor 4

血小板因子 4 的促动脉粥样硬化特性

• 批准号: 7184436
• 负责人: Bruce S Sachais
• 金额: $ 38.48万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-07 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7184436
• 关键词: Apolipoprotein E; Applications Grants; Arterial Fatty Streak; Atherosclerosis; Biological Models; Blood Platelets; Blood Vessels; Cell Adhesion; Cell surface; Cells; Characteristics; Clinical; Coagulation Process; Complex; Consensus; Data; Development; Education; Educational Curriculum; Educational process of instructing; Glycosaminoglycans; Grant; Health; In Vitro; Inflammation; Institution; International; Intervention; LDL-Receptor Related Protein 1; LDL-Receptor Related Proteins; Laboratories; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Metabolism; Methods; Modification; Mus; NF-kappa B; Pathway interactions; Phase; Platelet Activation; Platelet Factor 4; Play; Property; Protein Overexpression; Proteins; Public Health Schools; Reproductive Health; Research; Role; Testing; Training; Training Programs; United States National Institutes of Health; Universities; Vascular Diseases; Work; atherogenesis; base; behavioral/social science; chemokine; continuing medical education; design; health training; in vitro Model; in vivo; insight; lipid metabolism; multidisciplinary; novel; oxidized low density lipoprotein; programs; receptor; reproductive; transcription factor

DESCRIPTION (provided by applicant): Atherosclerosis is complex vascular disorder involving the interplay between inflammation, coagulation and lipid metabolism. There is increasing evidence that platelet activation but may play important roles in the initiation and/or expansion of atherosclerotic lesions. As platelets contain diverse modulators of inflammation, cell adhesion and endothelial activation, elucidating the mechanisms by which platelets promote atherogenesis may offer novel opportunities for intervention. My group has focused on the involvement of the platelet specific chemokine platelet factor 4 (PF4) in atherosclerosis. We have generated preliminary data in vivo that support the notion that PF4 is proatherogenic. Previous work from our laboratory has defined two receptor dependent pathways that may be responsible for PF4 atherogenicity. First, PF4 inhibits low density lipoprotein receptor (LDLR) dependent low density lipoprotein (LDL) degradation. This results in retention of LDL on the cell surface, which is prone to modification into oxidized LDL (ox-LDL). Second, PF4 activated NF-kB (a transcription factor involved in atherosclerosis and inflammation) via the LDL receptor related protein (LRP). The overriding hypothesis of this proposal is that PF4 activates one or both of these pathways to promote atherosclerotic lesion formation. We further posit that PF4 tetramers oligomerize in the presence of cell surface glycosaminoglycans (GAGs) before activation of the LDLR and/or LRP pathways. To test this hypothesis, we will study the effect of PF4 on atherosclerosis in vivo and elucidate its mechanism of action both in vivo and on vascular cells using in vitro model systems through three related Specific Aims: SA I: "Structural features of PF4 that contribute to proatherogenicity" will further dissect the details of these pathways in vitro, focusing on structural characteristics of PF4. SA II: "Characterize the effects of PF4 on lipoprotein metabolism and atherosclerosis in apoE-/- mice" will expand our characterization of apoE-/- mice lacking PF4, as well as to understand the implications of PF4 overexpression in apoE-/- mice. SA III: "Mechanism of PF4 proatherogenicity in vivo" will examine the importance of both the LDLR and LRP pathways for PF4 mediated atherogenesis. These studies will provide novel insights into the role of PF4, the most abundant protein released by activated platelets, on the development of atherosclerosis, delineate the pathways by which this occurs in vivo, and suggest potential methods to intervene in atherogenesis

描述（由申请人提供）：动脉粥样硬化是一种复杂的血管疾病，涉及炎症、凝血和脂质代谢的相互作用。越来越多的证据表明，血小板活化可能在动脉粥样硬化病变的发生和/或扩大中起重要作用。由于血小板含有多种炎症、细胞粘附和内皮活化调节剂，阐明血小板促进动脉粥样硬化形成的机制可能为干预提供新的机会。我的团队专注于血小板特异性趋化因子血小板因子4 （PF4）在动脉粥样硬化中的作用。我们已经在体内产生了初步数据，支持PF4是促动脉粥样硬化的概念。我们实验室之前的工作已经确定了两种受体依赖途径，可能导致PF4动脉粥样硬化。首先，PF4抑制低密度脂蛋白受体（LDLR）依赖性低密度脂蛋白（LDL）降解。这导致LDL滞留在细胞表面，这很容易被修饰成氧化LDL （ox-LDL）。其次，PF4通过LDL受体相关蛋白（LRP）激活NF-kB（一种参与动脉粥样硬化和炎症的转录因子）。该建议的最重要假设是，PF4激活这些途径中的一个或两个，以促进动脉粥样硬化病变的形成。我们进一步假设，在激活LDLR和/或LRP途径之前，PF4四聚体在细胞表面糖胺聚糖（GAGs）存在下寡聚。为了验证这一假设，我们将研究PF4在体内对动脉粥样硬化的影响，并通过三个相关的特定目的，阐明其在体内和对血管细胞的作用机制：SA I：“PF4的结构特征有助于促动脉粥样硬化”将进一步剖析这些体外途径的细节，重点关注PF4的结构特征。SA II：“表征PF4对apoE-/-小鼠脂蛋白代谢和动脉粥样硬化的影响”将扩展我们对缺乏PF4的apoE-/-小鼠的表征，以及了解apoE-/-小鼠中PF4过表达的含义。SA III：“体内PF4致动脉粥样硬化的机制”将研究LDLR和LRP途径在PF4介导的动脉粥样硬化中的重要性。这些研究将为PF4（活化血小板释放的最丰富的蛋白质）在动脉粥样硬化发展中的作用提供新的见解，描绘其在体内发生的途径，并提出干预动脉粥样硬化的潜在方法