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: 7038742
• 负责人: Bruce S Sachais
• 金额: $ 39.63万
• 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/7038742
• 关键词: atherosclerosis; cell membrane; clinical research; human tissue; inflammation; laboratory mouse; low density lipoprotein; low density lipoprotein receptor; mucopolysaccharides; nuclear factor kappa beta; oxidized lipid; platelet activation; platelet factor 4; protein degradation; protein structure function; receptor binding; vascular endothelium

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）：动脉粥样硬化是复杂的血管疾病，涉及炎症，凝结和脂质代谢之间的相互作用。越来越多的证据表明，血小板激活，但可能在动脉粥样硬化病变的启动和/或扩展中起重要作用。由于血小板包含炎症，细胞粘附和内皮激活的各种调节剂，因此阐明了血小板促进动脉粥样硬化的机制可能为干预提供新的机会。我的小组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参与。我们在体内产生了初步数据，该数据支持PF4具有促进性的观念。我们实验室的先前工作定义了可能导致PF4动脉粥样硬化性的两种受体依赖性途径。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。这会导致LDL在细胞表面上保留，这很容易修饰为氧化的LDL（OX-LDL）。其次，PF4通过LDL受体相关蛋白（LRP）激活了NF-KB（参与动脉粥样硬化和炎症的转录因子）。该提议的主要假设是PF4激活了这两种途径，以促进动脉粥样硬化病变的形成。我们进一步认为，在激活LDLR和/或LRP途径之前，PF4四聚体在存在细胞表面糖胺聚糖（GAGS）的情况下会寡聚。 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：“表征PF4对APOE - / - 小鼠中脂蛋白代谢和动脉粥样硬化的影响”将扩大我们对缺乏PF4的APOE - / - 小鼠的表征，并了解PF4过表达对APOE - / - 小鼠的影响。 SA III：“体内PF4促进性的机制”将检查LDLR和LRP途径对PF4介导的动脉粥样硬化的重要性。这些研究将为PF4的作用提供新的见解，PF4是活化血小板释放的最丰富蛋白，在动脉粥样硬化的发展中，描述了体内发生的途径，并提出了干预动脉粥样硬化的潜在方法