ABCA1/G1 and LXRs in Atherogenesis

尽管LDL降低疗法取得了成功，但仍需要新的治疗方法来降低LDL的水平。 残余动脉粥样硬化性心血管疾病的巨大负担。增加有益的HDL 功能是一种潜在的方法。HDL输注疗法和小分子LXR激活剂， 诱导巨噬细胞泡沫细胞胆固醇流出并减轻动物动脉粥样硬化 模型然而，潜在的保护机制尚未完全理解， 延缓了临床发展。胆固醇流出途径似乎发挥抗动脉粥样硬化作用， 通过抑制骨髓细胞中的炎症反应来发挥作用。胆固醇外流到 ApoA-1和HDL由ATP结合盒转运蛋白ABCA 1和ABCG 1促进， 这是由LXR诱导的。我们最近在骨髓细胞缺乏的小鼠中的研究， 转运蛋白已经揭示了胆固醇流出途径在抑制胆固醇转运中的主要作用。 炎性小体这些小鼠在巨噬细胞和中性粒细胞中显示炎性小体活化。 出乎意料的是，他们也显示出突出的中性粒细胞胞外陷阱（NET）的病变。 炎性小体成分的缺乏减少了病变面积并消除了NETs，显示出 第一次发现炎性小体激活促进了病变性NETosis。最近的CANTOS审判 已经强调了炎症小体激活和IL-1b产生在人类中的重要性， 冠心病其他研究表明NETosis在动脉粥样硬化形成和斑块中的作用 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 这些过程具有主要的翻译潜力，特别是在ABCA 1/G1被 高密度脂蛋白（HDL）水平低，如2型糖尿病。本提案的目的是 评价胆固醇流出途径与致动脉粥样硬化炎症的联系机制。目标1将 探索ABCA 1/G1介导的胆固醇流出与炎性小体激活的联系机制， 动脉粥样硬化和NETosis。目的2探讨rHDL-1的作用机制及意义。 介导的胆固醇流出巨噬细胞炎症。目标3将评估新机制 将LXR激活与抑制致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，刺激新的治疗方法的发展， 动脉粥样硬化

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.