应用OCT研究胆固醇结晶调控NETosis/IL-1β表达活化促进易损斑块形成的机制

易损斑块破裂是急性心肌梗死（AMI）的主要病理机制，降脂治疗不能完全防控AMI的发生。新近CANTOS研究表明以IL-1β为靶点的抗炎治疗显著降低AMI等心血管不良事件，奠定了抗炎治疗在冠心病防治中的重要地位。然而，斑块内IL-1β表达活化的具体机制和以IL-1β为靶点的抗炎治疗对易损斑块稳定性的影响尚未明确。课题申请人前期在体应用光学相干断层成像（OCT）技术发现胆固醇结晶与中性粒细胞胞外诱捕网络（NETs）水平、巨噬细胞聚集、以及易损斑块破裂密切相关，且NETs对巨噬细胞IL-1β生成有级联放大作用。因此，我们推测胆固醇结晶调控NETs生成和IL-1β表达活化是促进易损斑块形成的重要机制。本项目将联合OCT和分子生物学技术，从细胞到动物水平揭示胆固醇结晶介导斑块炎症反应的机制及其在易损斑块形成中的作用。通过干预胆固醇结晶致炎过程的关键环节，有望为稳定易损斑块和防治AMI带来新的曙光。

Rupture of vulnerable plaque is the leading pathology mechanism of acute myocardial infarction. Lipid-lowering therapy can not completely prevent AMI. The recent CANTOS trial has demonstrated that anti-inflammatory treatment targeting IL-1β significantly reduces adverse cardiovascular events including acute myocardial infarction, laying an important role in prevention and treatment of coronary heart disease. However,the specific mechanism of IL-1β expression and activation in plaque, and the effect of anti-inflammatory therapy targeting IL-1β on vulnerable plaque have not been clearly defined. In previous research work, we demonstrated that cholesterol crystal is closely related to the level of neutrophil extracellular traps (NETs), macrophages accumulation, and vulnerable plaque rupture in vivo by using optical coherence tomography (OCT). NETs has a cascade amplification effect on macrophage IL-1β generation. Therefore, we hypothesized that NETs generation and IL-1β expression and activation mediated by cholesterol crystal is the critical mechanism for vulnerable plaque formation. The present project will combine using OCT and molecular biology technology to reveal the mechanisms of cholesterol crystal mediated inflammation and its effect on vulnerable plaque formation from cell to animal level. It is reasonable to speculate that our project will bring new dawning for stabilizing vulnerable plaque and preventing AMI by intervening the key link of inflammatory response mediated by cholesterol crystal.