IL-33/ST2信号通路抑制炎症小体激活减少主动脉夹层发生的机制研究

Aortic dissection (AD) showed features of degeneration and dialation, with its mortality up to 90% once ruptured. Several signaling pathways, like the NLRP3 inflammasome pathway plays a critical role in AD formation, while the endogenous protective molecular mechanism remains unclear. Our previous study showed that sST2 was an independent biomarker for early diagnosis of AD. ST2 deficiency aggravated AD formation and aneurysm rupture, and IL33 treatment decreased the maximal diameter and severity of AD and inhibited NLRP3 expression, which suggested the protective role of IL33/ST2 in AD formation. Moreover, there were accumulated smooth muscle cells apoptosis in angiotensin II infused-ST2 knockout mouse aorta, which could be blocked by IL33 treatment. Furthermore, the expression of IL33 was upregulated in vascular fibroblasts in case of mechanical overload. Therefore, we hypothesized that IL33/ST2 deficiency upregulated NLRP3 inflammasome activity after angiotensin II infusion, and downregulated MAPKp38/JNK/ERK pathway to promote smooth muscle cell apoptosis, leading to AD. In the present study, we will induce AD formation in wild type and ST2 knockout mice, as well as ST2 conditional knockout mice to clarify the protective role of IL33/ST2 in Ang II infusion-induced AD formation by performing bone marrow transplantation, echography, pathological analysis and quantitative and modification proteome analysis in vitro.

主动脉夹层（AD）呈血管壁退行性改变及扩张，破裂后死亡率达90%。炎症小体过度激活促进AD发生，但内源性保护机制研究尚少。我们前期发现ST2是AD特异标志物，ST2敲除显著增加AD发生及破裂率，而IL33/ST2活化可抑制AD形成及NLRP3炎症小体激活，提示IL33/ST2对AD具有保护作用；进而发现ST2敲除引发平滑肌细胞凋亡，而IL33/ST2活化可激活MAPKp38/JNK/ERK通路，上调抗凋亡基因，减轻凋亡，我们提出假设：IL33/ST2失活可能激活NLRP3炎症小体及下调MAPK通路调节凋亡而引起AD。本研究拟在野生、ST2敲除及条件敲除小鼠中诱导AD，结合病理、分子生物学、蛋白质组学等分析，明确高血压如何诱导IL33/ST2活性改变，IL33/ST2如何抑制炎症小体活化、上调MAPK通路，从而抑制平滑肌细胞表型转化、凋亡，维持细胞外基质稳定，保护AD发生的具体机制。

主动脉夹层是主要的心血管急危重症，指由于内膜局部撕裂，受到血液冲击后逐步剥离扩展，在动脉内形成真假两腔，从而导致撕裂样疼痛、主动脉破裂，破裂后死亡率达90%以上。主动脉夹层发病率极速增加，经济负担严重。然而目前临床上缺乏有效的药物干预及防治靶点。多种因素参与主动脉夹层的发病，包括遗传因素、高血压以及其他心血管疾病危险因素，主要病理改变包括平滑肌细胞丢失和表型转化，炎症反应，细胞外基质断裂等。在遗传与环境因素的交互作用下，代谢分子响应内外环境因素刺激，可快速反映疾病的进程。本项目首先利用GWAS公共数据及临床大队列样本发现sST2相关基因IL1R1单核苷酸多态性rs13019803C是主动脉夹层的新易感基因，解释了患者发病后循环sST2水平的差异，有助于识别疾病高风险个体，开发新的诊疗策略。基于ST2在主动脉夹层发病中的重要作用，研究进一步发现激活IL-33/ST2轴在胸主动脉夹层早期有显著的治疗作用，同时设计并合成了一种靶向荧光纳米载体，联合IL-33治疗可以实现在胸主动脉夹层发病早期的准确诊断和有效治疗。在此基础之上，建立胸痛快速鉴别诊断的新系统，进一步研发了基于光晶和适配体特异性识别sST2的检测新系统。研究发现血清sST2水平与A型主动脉夹层术前器官灌注不良及院内不良事件及扩张型心肌病的预后相关。此外脂质代谢组学分析发现，主动脉夹层患者/小鼠中脂质水平与健康对照明显不同，激活IL-33/ST2轴有利于血管内膜稳态维持，为防治主动脉夹层提供新的可能。总之，本项目确定了IL-33/ST2轴在主动脉夹层发生发展中的重要作用，为主动脉夹层的识别诊断、有效治疗提供理论基础。