C1q/TNF-related protein 9调控平滑肌细胞程序性坏死抑制动脉粥样硬化的机制研究

Atherosclerosis (AS) plaque stability is an important prognostic factor in patients with coronary heart disease, inflammation plays an important role in AS progression and vulnerable plaque formation. As the most important component of AS plaque, the functional status of smooth muscle cells (VSMCs) is closely related to inflammation. Previous studies have found that there are a large number of necroptosis VSMCs in advanced plaques, which cause and aggravate inflammation. We speculate that necroptosis VSMCs are the key factors to promote the development of AS and the formation of vulnerable plaques, and regulating the necroptosis of VSMCs may be a new direction in the treatment of AS, but there is no relevant research at present. ROS is an important target for inhibiting necroptosis. Our previous work has proved that anti-inflammatory adipokine CTRP9 can promote the expression of antioxidant enzymes and inhibit ROS, which may play a role in regulating the necroptosis VSMCs. This project aims to explore the role of necroptosis VSMCs in AS via establishing transgenic model animals, and confirm that CTRP9 can repress AS through regulating necroptosis VSMCs, also it is of great significance to clarify whether necroptosis VSMCs can be used as a new intervention target for AS and the therapeutic effect of CTRP9 on AS.

动脉粥样硬化（AS）斑块稳定性是决定冠心病患者预后的重要因素，炎症在AS进展及易损斑块形成中发挥重要的作用。作为斑块最主要的成分，平滑肌细胞（VSMCs）功能状态与炎症反应密切相关。我们前期研究发现进展期斑块内存在大量程序性坏死的VSMCs，程序性坏死的细胞引起并加重炎症反应，我们推测程序性坏死的VSMCs是AS发展及易损斑块形成的关键促进因素，调控平滑肌细胞程序性坏死可能是治疗AS的新方向，但目前尚无相关研究。ROS是抑制细胞程序性坏死的重要靶点。我们前期工作证明抗炎性脂肪因子CTRP9可促进抗氧化酶表达，抑制ROS，可能具有调控VSMCs程序性坏死的作用。本项目拟通过构建转基因模式动物，探索VSMCs程序性坏死在AS中的作用，并证实CTRP9可通过调控VSMCs程序性坏死抑制AS。本项目对于明确VSMCs程序性坏死是否可作为AS新的干预靶点及CTRP9对于AS的治疗作用具有重要的意义。

动脉粥样硬化（AS）斑块稳定性是决定冠心病患者预后的重要因素，CANTOS研究发现抗炎治疗显著降低心血管不良事件发生率，说明抗炎治疗是目前标准化治疗方案下解决CVD 患者残余心血管不良事件风险的最有效手段。作为斑块最主要的成分，平滑肌细胞（VSMCs）源性细胞的功能状态与炎症反应密切相关，且易损斑块内存在大量程序性坏死的VSMCs源性细胞，进一步加重炎症反应，但何因素诱导其发生程序性坏死尚不明确。本项目中，我们证实较低剂量的ox-LDL即可引起VSMCs源性泡沫细胞发生程序性坏死，促进炎症因子及促AS进展相关分子表达，揭示了斑块微环境内VSMCs源性泡沫细胞程序性坏死的原因；应用抗氧化剂可抑制ox-LDL对VSMCs源性泡沫细胞的损伤作用，说明ox-LDL诱导VSMCs源性泡沫细胞程序性坏死是通过氧化应激途径。脂肪因子CTRP9通过激活AMPK调节抗氧化酶表达，呈剂量依赖性的抑制ox-LDL引起的VSMCs源性泡沫细胞程序性坏死；体内过表达CTRP9可减少斑块内程序性坏死相关蛋白表达，减少斑块面积，稳定斑块，可能成为治疗CVD的新方法。同时我们在研究中发现AS斑块中存在大量衰老细胞，衰老标志物与程序性坏死染色存在部分重叠。说明衰老与VSMCs源性泡沫细胞程序性坏死可能存在潜在联系，因此我们应用高通量测序检测96W和8W龄C57小鼠主动脉中lncRNAs和mRNAs的表达，筛选出差异表达明显的lncRNA与mRNA并进行了后续的实验验证。本项目着眼于“降低冠心病残余风险”这一临床难题，从VSMCs源性泡沫细胞的程序性坏死为切入点，应用模式动物、高通量测序、分子生物学、免疫学、病理学等多种实验手段，从细胞、动物层面分别阐述VSMCs源性泡沫细胞的程序性坏死的机制并探讨CTRP9的治疗效果，本项目的成果开展为降低冠心病残余风险提供了重要的理论依据。

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