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 LDL 的疗法取得了成功，但仍需要新的疗法来降低 残留动脉粥样硬化性心血管疾病的巨大负担。增加有益的 HDL 函数是一种潜在的方法。 HDL 输注疗法和小分子 LXR 激活剂， 诱导巨噬细胞泡沫细胞中胆固醇流出并减少动物动脉粥样硬化 模型。然而，潜在的保护机制尚不完全清楚，这 延迟了临床开发。胆固醇流出途径似乎具有抗动脉粥样硬化作用 通过抑制骨髓细胞的炎症反应来发挥作用。胆固醇流出 ApoA-1 和 HDL 由 ATP 结合盒转运蛋白 ABCA1 和 ABCG1 促进， 这是由 LXR 诱导的。我们最近对患有这些骨髓细胞缺陷的小鼠进行的研究 转运蛋白揭示了胆固醇流出途径在抑制 炎症小体。这些小鼠在巨噬细胞和中性粒细胞中显示出炎症小体激活。 出乎意料的是，他们还在病变中显示出明显的中性粒细胞胞外陷阱（NET）。 炎症小体成分的缺乏减少了病变面积并消除了 NET， 炎症小体激活首次促进病变 NETosis。最近的 CANTOS 审判 强调了人类炎症小体激活和 IL-1b 产生的重要性 冠心病。其他研究表明 NETosis 在动脉粥样硬化和斑块中发挥作用 不稳定。因此，我们的研究表明 HDL 和胆固醇流出途径可以抑制 这些过程具有重大的转化潜力，特别是在 ABCA1/G1 存在的情况下 受抑制且 HDL 水平较低，例如 2 型糖尿病。该提案的目标是 评估胆固醇流出途径与致动脉粥样硬化炎症之间的联系机制。目标1将 探索 ABCA1/G1 介导的胆固醇流出与炎症小体激活之间的联系机制， 动脉粥样硬化和 NETosis。目标2将探讨rHDL-的机制和意义 介导巨噬细胞炎症中的胆固醇流出。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 提供新颖的机制见解，刺激新疗法的开发 动脉粥样硬化。