阿托伐他汀通过调节SIRT1/NF-κB信号通路对支架内新生动脉粥样硬化影响的研究

The formation of in-stent neoatherosclerosis (ISNA), which can result in myocardial infarction and sudden death, still occur after coronary stent implantation. ISNA can be identified effectively and diagnosed accurately by imaging of optical coherence tomography (OCT), However, related studies showed that the occurrence and development of ISNA had a different pathological basis from endovascular atherosclerosis. The common using of statin drugs regulated the inflammatory response during the development of endovascular atherosclerosis through SIRT1/NF-κB pathway, but its influence on ISNA is still unclear. The purposes of this project are to explore the changes of protein expression in SIRT1/NF-κB pathway in the second generation of drug-eluting stents neoatherosclerosis animal models with combining OCT technology, pathology and molecular biology detection technology, to research the mechanism of the pathway in the development of ISNA, to look for the key biomarkers in the development process, to evaluate the effect of different intensities of statin on ISNA through the SIRT1/NF-κB pathway and to find the key cell targets. This project can provide new ideas for solving the occurrence of adverse events in clinical stent implantation and the application of statin drugs.

冠状动脉支架植入后仍可发生支架内新生动脉粥样硬化（ISNA）的形成，从而引发心肌梗死，甚至猝死等不良事件。我们通过光学相干断层成像（OCT）技术可对ISNA进行有效识别和准确诊断，但相关研究表明ISNA的发生发展有着不同于血管内动脉粥样硬化的病理基础。临床常用的他汀类药物通过SIRT1/NF-κB信号通路调控血管内动脉粥样硬化发生发展过程中的炎症反应，而其对ISNA的影响目前未见相关研究。本研究拟通过结合OCT技术、病理学及分子生物学检测技术，在第二代药物洗脱支架的ISNA动物模型中，探索SIRT1/NF-κB信号通路相关蛋白表达的变化规律，研究该信号通路在ISNA发生发展过程的作用机制，寻找该过程中关键的生物标记物，评价不同强度他汀类药物通过SIRT1/NF-κB信号通路对ISNA的影响，并判定其中的关键细胞靶点。本项目可为解决临床支架植入后不良事件的发生及他汀类药物的应用提供新的思路。

课题实现支架内兔新生动脉粥样硬化模型，高脂饮食组支架内动脉粥样硬化发生率（节段发生率）较高，且炎症积分与损伤积分较高。支架植入后支架内膜中平滑肌细胞中SIRT1/NF-κB信号通路相关表达在SIRT1 抑制剂组明显降低。通过血样等副产物得到外源性硫化氢能有效抑制缺氧诱导的平滑肌细胞的增殖、迁移和氧化应激的增加。通过代谢组学选定了十七个潜在生物标志物中的三个，犬尿素、胆碱、鞘氨醇，使用血浆检测有可能评价患者在体支架内新生动脉粥样硬化诊断情况。