ABCA1/G1 and LXRs in Atherogenesis

ABCA1/G1 和 LXR 在动脉粥样硬化形成中的作用

• 批准号: 10171606
• 负责人: ALAN richard TALL
• 金额: $ 51.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171606
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Animal Model; Antiatherogenic; Apolipoprotein A-I; Area; Arterial Fatty Streak; Atherosclerosis; Bone Marrow; Bone Marrow Transplantation; CASP1 gene; Cardiovascular Diseases; Caspase; Cholesterol; Cleaved cell; Coronary heart disease; Development; Endothelium; Foam Cells; Gene Expression; Genes; Goals; Grant; Hematopoietic; Hematopoietic stem cells; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Knock-out; LXRalpha protein; Lesion; Leukocytes; Link; Low-Density Lipoproteins; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Neutrophil Infiltration; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Peritonitis; Process; Production; Residual state; Role; S100A8 gene; Secondary to; Testing; Time; Work; Zymosan; atherogenesis; clinical development; experimental study; extracellular; insight; macrophage; migration; monocyte; neutrophil; novel; reconstitution; recruit; small molecule; success; transcriptome sequencing

Despite the success of LDL lowering therapies there is a need for new treatments to reduce the large burden of residual atherosclerotic cardiovascular disease. Increasing beneficial HDL functions is one potential approach. HDL infusion therapies and small molecule LXR activators, induce cholesterol efflux from macrophage foam cells and reduce atherosclerosis in animal models. However, the underlying protective mechanisms are incompletely understood and this has delayed clinical development. Cholesterol efflux pathways appear to exert anti-atherogenic effects by suppressing inflammatory responses in myeloid cells. The efflux of cholesterol to ApoA-1 and HDL is facilitated by the ATP binding cassette transporters ABCA1 and ABCG1, which are induced by LXRs. Our recent studies in mice with myeloid cell deficiency of these transporters have revealed a major role of cholesterol efflux pathways in suppressing the inflammasome. These mice showed inflammasome activation in macrophages and neutrophils. Unexpectedly, they also displayed prominent neutrophil extracellular traps (NETs) in lesions. Deficiency of inflammasome components reduced lesion area and abolished NETs, showing for the first time that inflammasome activation promotes lesional NETosis. The recent CANTOS trial has highlighted the importance of inflammasome activation and IL-1b production in human coronary heart disease. Other studies have shown a role of NETosis in atherogenesis and plaque instability. Thus, our studies showing that HDL and cholesterol efflux pathways can suppress these processes have major translational potential, especially in conditions where ABCA1/G1 are suppressed and HDL levels are low, such as Type 2 diabetes. The goal of this proposal is to evaluate mechanisms linking cholesterol efflux pathways to atherogenic inflammation. Aim 1 will explore mechanisms linking ABCA1/G1-mediated cholesterol efflux to inflammasome activation, atherogenesis and NETosis. Aim 2 will explore the mechanisms and significance of rHDL- mediated cholesterol efflux in macrophage inflammation. Aim 3 will assess new mechanisms connecting LXR activation to suppression of atherogenic inflammation. These studies may provide novel mechanistic insights stimulating the development of new treatments for atherosclerosis.

尽管降低低密度脂蛋白的治疗取得了成功，但仍需要新的治疗方法来减少 遗留动脉粥样硬化性心血管疾病负担大。增加有益的高密度脂蛋白 函数是一种潜在的方法。高密度脂蛋白输注疗法和小分子LXR激活剂， 诱导巨噬细胞泡沫细胞胆固醇外流减轻动物动脉粥样硬化 模特们。然而，潜在的保护机制还不完全清楚，这 延缓了临床的发展。胆固醇外流途径似乎发挥了抗动脉粥样硬化的作用 抑制髓系细胞炎症反应的作用。胆固醇的外流到 载脂蛋白A-1和高密度脂蛋白由三磷酸腺苷结合盒转运体ABCA1和ABCG1促进， 它们是由LXRs诱导的。我们最近在髓系细胞缺乏症小鼠中的研究 转运蛋白已经揭示了胆固醇外流途径在抑制 炎症者。这些小鼠在巨噬细胞和中性粒细胞中表现出炎性小体激活。 出乎意料的是，他们还在病变中显示了明显的中性粒细胞外陷阱(Net)。 炎性小体成分缺乏，病变面积缩小，网状结构消失，表现为 首次发现炎性小体激活促进皮损性网织红细胞增多症。最近的《诗篇》审判 已经强调了人类炎症体激活和IL-1b产生的重要性 冠心病。其他研究表明，NETsis在动脉粥样硬化形成和斑块形成中起作用 不稳定。因此，我们的研究表明，高密度脂蛋白和胆固醇外流途径可以抑制 这些过程具有很大的翻译潜力，特别是在ABCA1/G1 抑制和高密度脂蛋白水平低，如2型糖尿病。这项提议的目标是 评估将胆固醇外流途径与动脉粥样硬化炎症联系起来的机制。目标1将 探索ABCA1/G1介导的胆固醇外流与炎性小体激活之间的联系机制 动脉粥样硬化的发生与网络病变。目的2探讨rHDL2的作用机制和意义。 巨噬细胞炎症中介导的胆固醇外流。目标3将评估新机制 将LXR激活与抑制动脉粥样硬化炎症联系起来。这些研究可能 提供新的机制见解，刺激开发新的治疗方法 动脉硬化。