基于FABP4介导的血管内皮-平滑肌细胞通讯探讨舒脉胶囊干预外周动脉介入后再狭窄的作用机制

Postoperative restenosis (PRS) is the main challenge after interventional treatment of peripheral arterial disease (PAD). Chinese medicine may be a new strategy to solve the drug resistance and side effects of mainstream anti-restenosis drugs. The curative effect of Shumai Capsule in the clinical treatment of PAD and PRS is exact. Preliminary studies have shown that Shumai Capsule can inhibit the process of atherosclerosis and neointimal hyperplasia which is the key pathological process of PAD-PRS,and the different two medicine group of shumai capsule have a opposite effect, but combined with synergies.New evidence shows that FABP4 is highly ectopic expressed in vascular endothelial cells after injury and mediates the interaction between vascular endothelial cells and smooth muscle cells. This suggests that FABP4, which mediates communication between vascular endothelium and smooth muscle cells, may be a key target for Shumai capsule to play an important role in anti-restenosis. In this study, in vivo experiments and in vitro experiments were carried out in animal models of Iliac Artery Balloon Injury, vascular endothelial cells, vascular smooth muscle cells and FABP4, from animal, tissue, cell, protein and gene levels.The purpose is to study the mechanism of Shumai capsule against PAD-PRS and to interpret the scientific connotation of Shumai Capsule with warming yang, invigorating qi and promoting blood circulation, and lay the foundation for further basic research and clinical application of Shumai capsule.

术后再狭窄（PRS）是外周动脉病（PAD）介入治疗后面临的主要难题，中药可能是解决一线抗再狭窄药的耐药、副作用问题的新策略。舒脉胶囊在临床用于PAD及PRS的治疗，前期研究表明，舒脉胶囊可抑制PAD-PRS的关键病理过程-动脉硬化与新生内膜增生，全方效力优于拆方。新证据显示脂肪酸结合蛋白4（FABP4）在介入损伤后血管内皮细胞中高异位表达，介导了血管内皮与平滑肌细胞交流通讯。这提示FABP4可能是舒脉胶囊抑制再狭窄的关键靶点。本研究将通过体内实验与体外实验，以髂动脉球囊损伤大鼠模型、血管内皮细胞、血管平滑肌细胞、FABP4为研究对象，从个体、组织、细胞、蛋白、基因水平研究舒脉胶囊抗PAD-PRS的作用机制，诠释舒脉胶囊温补肾阳、益气活血的科学内涵，为舒脉胶囊进一步的基础研究及临床应用奠定基础。

背景：舒脉胶囊通过下调FABP4在损伤后血管内皮细胞中的异位表达和分泌，影响血管内皮-平滑肌细胞的胞间通讯，进而调节再内皮化和新生内膜增生，最终抑制外周动脉介入后再狭窄。.主要研究内容：以舒脉胶囊为干预手段，以髂动脉介入损伤大鼠及VECs、VSMCs、FABP4研究工具，设计体内、体外两个角度研究，并使用过表达载体转染重组细胞的方法，从动物、细胞、蛋白、基因水平进行研究，观察舒脉胶囊对髂动脉损伤后大鼠行为学、血管影像学及新生内膜增生、再内皮化程度，检测VSMCs、VECs增殖、迁移情况，Erk/MAPK信号通路及信使蛋白c-jun、c-myc的活化情况，以及循环、组织FABP4、PPARγ、MMPs的表达情况。.关键数据结果：.（一）体内实验：模型组、舒脉胶囊组、FABP4抑制剂组左髂动脉内膜增厚,内膜厚度和管腔直径均大于假手术组(P<0.05),并且舒脉胶囊组内膜厚度小于模型组(P<0.05)；模型组、舒脉胶囊组、FABP4抑制剂组血清NO水平低于假手术组（P＜0.05），舒脉胶囊组、FABP4抑制剂组血清NO水平高于模型组(P<0.05)；舒脉胶囊组、FABP4抑制剂组血清FABP4水平低于模型组(P<0.05)；舒脉胶囊组、FABP4抑制剂组中左髂动脉血管组织中FABP4蛋白低于模型组(P<0.05)。.（二）体外实验：舒脉胶囊通过靶向下调FABP4、抑制FABP4基因及MAPK通路相关蛋白的表达，提高NO、MMP-1、MMP-2、eNOs、VEGF的生成，增强血管内皮细胞的迁移和增殖能力，降低血管平滑肌细胞的迁移和增殖能力，抑制介入术后血管内膜增生,从而改善血管内皮功能。.科学意义：通过以上研究，可以明确舒脉胶囊防治外周动脉病介入后再狭窄的具体作用机制，为临床应用和开发提供实验依据，为深入研究舒脉胶囊及温补肾阳、益气活血理论奠定基础。