Macrophage Death in Plaque Vulnerability

斑块脆弱性中的巨噬细胞死亡

• 批准号: 7160713
• 负责人: Ira A Tabas
• 金额: $ 47.91万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7160713
• 关键词: BCL2 gene /protein; apolipoprotein E; apoptosis; atherosclerosis; atherosclerotic plaque; blood lipoprotein; cell cell interaction; cellular pathology; cholesterol; gene targeting; genetic susceptibility; genetically modified animals; histopathology; inflammation; laboratory mouse; macrophage; membrane transport proteins; mitogen activated protein kinase; molecular pathology; pathologic process; phagocytic dysfunction; phagocytosis; tissue /cell culture; tumor necrosis factor alpha

Two important features of atherosclerotic plaque progression are the presence of large necrotic cores, which arise from macrophage (Mf) death, and inflammation. In addition, advanced lesional Mfs accumulate large amounts of free cholesterol (FC). Using cultured Mfs, we have shown that FC loading induces inflammatory cytokines and activation of p38 MARK and the unfolded protein response (UPR). This is followed by down-regulation of the anti-apoptotic protein Bcl-2, induction of UPR/p38-mediated apoptosis, and, in the absence of phagocytosis, secondary cellular necrosis. Importantly, markers of the UPR are associated with Mfs in advanced atherosclerotic lesions. In this context, we hypothesize that Mf apoptosis and inflammatory responses in advanced atherosclerotic lesions, coupled with defective phagocytic clearance of the apoptotic cells, promote progression to the vulnerable plaque. To test this hypothesis, we will explore the role of the MKK3-p38 MAP kinase pathway in cholesterol-induced Mf death in vitro and in vivo (Aim I); investigate the FC-induced inflammatory response and the consequences of phagocytic clearance of FC-loaded Mfs (Aim II); and determine the role of Bcl-2 in FC-induced Mf apoptosis and plaque vulnerability (Aim III). Each Aim will consist of a series of mechanistic experiments using cultured Mfs and, to determine relevance to plaque morphology, in-vivo experiments using mice with targeted mutations in critical genes in the aforementioned pathways: macrophage p38; the apoptotic cell phagocytic receptor Mer; and macrophage Bcl-2. These studies will involve essential interactions with each of the other projects of the program as well as use of the Lesion Analysis Core and biostatistic and QPCR core functions. The ultimate goal is to elucidate how FC-induced apoptosis and inflammatory cytokine production in Mfs and phagocytic clearance of apoptotic cells affect those late lesional characteristics that eventually lead to atherothrombotic vascular occlusion. New insights in this area may suggest new therapeutic strategies to combat cardiovascular disease.

动脉粥样硬化斑块进展的两个重要特征是存在大坏死核的存在，即 这是由巨噬细胞（MF）死亡和炎症引起的。此外，高级病变MFS积累 大量游离胆固醇（FC）。使用培养的MFS，我们表明FC加载诱导 炎症细胞因子和p38 mark的激活和展开的蛋白质反应（UPR）。这是 然后下调抗凋亡蛋白Bcl-2，诱导UPR/p38介导的凋亡， 并且，在没有吞噬作用的情况下，继发性细胞坏死。重要的是，UPR的标记是 与高级动脉粥样硬化病变中的MF相关。在这种情况下，我们假设MF凋亡 和晚期动脉粥样硬化病变中的炎症反应，再加上缺陷的吞噬细胞 凋亡细胞的清除率促进易受伤害的斑块的进展。为了检验这一假设，我们 将探索MKK3-P38 MAP激酶途径在胆固醇诱导的MF死亡中的作用 Vivo（AIM I）;研究FC引起的炎症反应和吞噬的后果 FC负载MF的清除（AIM II）；并确定Bcl-2在FC诱导的MF凋亡和斑块中的作用 脆弱性（AIM III）。每个目标都将包括使用培养的MFS的一系列机械实验，并且 为了确定与斑块形态的相关性，使用具有靶向突变的小鼠的体内实验 上述途径中的关键基因：巨噬细胞p38；凋亡细胞吞噬受体 梅和巨噬细胞Bcl-2。这些研究将涉及与其他每个项目的基本互动 该程序以及病变分析核心以及生物统计学和QPCR核心功能的使用。这 最终目标是阐明FC诱导的MFS中的凋亡和炎症细胞因子产生如何 凋亡细胞的吞噬清除率会影响那些最终导致的病变特征 动脉瘤血栓性血管阻塞。在这一领域的新见解可能会提出新的治疗策略 战斗心血管疾病。