光/声双模成像研究焦油通过AHR/FasL/RIP轴介导的平滑肌细胞坏死性凋亡在斑块进展中的作用和机制

动脉粥样硬化（AS）中易损斑块破裂是急性冠脉综合征（ACS）的重要病理基础。大量研究发现吸烟是导致AS易损斑块形成的重要原因，而平滑肌细胞（SMC）大量死亡是易损斑块的重要特征，但其相关诱因及分子机制尚不清楚。我们前期研究发现香烟焦油可以加速ApoE-/-鼠AS斑块进展，并在体外诱导SMC发生特殊类型的死亡-坏死性凋亡。通过UPLC-MS分析我们发现焦油的主要成分为多环芳烃，其可以活化芳烃受体AHR促进Fas的转录，从而激活RIP介导的坏死性凋亡通路。因此，我们首次提出焦油通过AHR/FasL/RIP轴导致斑块内SMC发生坏死性凋亡，进而增加斑块易损性，使ACS事件风险升高。本项目将利用自主研发的光/声双模成像技术，阐明焦油促进平滑肌细胞坏死性凋亡增加斑块易损性的分子机制，并结合大动物模型证实AHR/FasL/RIP轴作为吸烟相关AS疾病干预靶点的转化价值，为临床ACS的防治提供新思路。

The rupture of vulnerable plaques in the progression of atherosclerosis (AS) is an important pathological mechanism of acute coronary syndrome (ACS). A large number of investigations have found that smoking is a significant factor leading to the formation of vulnerable plaques, while the death of numerous smooth muscle cells is an important feature of vulnerable plaques. However, the related causes of them and its molecular mechanism are still not clear. Our previous study has showed that tar, the main component of tobacco, could accelerate the progression of AS plaques in ApoE-/- mice. Tar could also induce a special type of death of smooth muscle cells in vitro - necroptosis. At our early stage, we used UPLC-MS to detect tar and found that the main component of tar is polycyclic aromatic hydrocarbons. AHR is the receptor of polycyclic aromatic hydrocarbons, whose activation can promote the transcription of Fas, and activate the necroptosis signal pathway mediated by RIP thereby. Therefore, for the first time we propose that tar leads to necroptosis of smooth muscle cells in plaques through the AHR/FasL/RIP axis, which increases plaque vulnerability and increases the risk of major adverse cardiac events. The aim of this project is to clarify the molecular mechanism of tar increasing plaque vulnerability by promoting necroptosis of smooth muscle cells. The self-developed optical/acoustic dual-mode imaging technology will be applied to large animal model. Such conduct transformational medical research will be performed to confirm the feasibility of AHR/FasL/RIP axis as a target for intervention of smoking-related AS diseases, and it is hopeful to provide a new strategy for prevention and treatment of ACS in clinical practice.