人参皂苷Re抗球囊损伤后血管狭窄及对血管平滑肌表型转化的机制研究

The serious cardiovascular disease, especially the Atherosclerosis (AS) and Postangioplasty Restenosis (RS) have imposed more and more threats on human health, which pathogenesis is intimal hyperplasia of vascular smooth muscle cells (VSMC). The antitumor drug-eluting stents have been used widely in clinical in order to inhibit intimal hyperplasia，however, it cause delayed covering in endothelial damage parts. So looking for a kind of drugs which can not only promote endothelial repairing but also inhibit VSMC proliferation is a ideal strategy for prevention and treating AS and RS. Ginsenoside Re (Re) is one of main active substance of Ginseng. Our previous experiments reveals Re can inhibit intimal proliferation caused by balloon-injured carotid artery of rat, but its mechanism is unknown. This study intends to confirm the resistance effect of Re on intimal hyperplasia of VSMC and explore its mechanism through testing the MAPK signaling pathway which influence VSMC phenotype transformation and NO system which promote endothelial repairing by using signaling pathway inhibitors, flow cytometry and western blotting within balloon-injured carotid artery model in vivo and vitro model of VSMC proliferation so as to provide theoretical basis for new drugs against AS and RS.

动脉粥样硬化（AS）及血管成形术后再狭窄（RS）等心血管疾患严重威胁人类生命健康。血管内膜增殖所致血管狭窄是此类疾病的最重要病理基础。临床常用抗肿瘤药物洗脱支架抑制内膜增殖，但造成损伤部位内皮修复延迟。故寻找一种既能促进损伤血管内皮修复又能抑制血管增殖的药物，是防治AS和RS理想的策略。人参皂苷Re（Re）为我国名贵中药材人参的主要活性物质之一。本课题组预实验发现，Re能抑制球囊损伤所致大鼠颈动脉内膜增殖，但其作用机制未明。本研究拟采用在体及离体VSMC增殖模型，以影响VSMC表型转化的MAPK信号通路，促进血管内皮修复的NO系统为切入点，利用信号通路抑制剂、流式细胞术、western blotting等方法，确证Re对血管内膜增殖的抑制作用，深入研究Re抗血管内膜增殖的作用机制，为研究阻断AS及RS疾病进展的新药提供重要的理论依据。

动脉粥样硬化（AS）及血管成形术后再狭窄（RS）等心血管疾患严重威胁人类生命健康。血管内膜增殖所致血管狭窄是此类疾病的最重要病理基础。临床常用抗肿瘤药物洗脱支架抑制内膜增殖，但造成损伤部位内皮修复延迟。故寻找一种既能促进损伤血管内皮修复又能抑制血管增殖的药物，是防治AS和RS理想的策略。人参皂苷Re（Re）为我国名贵中药材人参的主要活性物质之一。本课题组预实验已发现，Re能抑制球囊损伤所致大鼠颈动脉内膜增殖，但其作用机制未明。因此本研究采用在体及离体VSMC增殖模型，首先确证了Re对在体大鼠血管内膜增殖具有抑制作用，同时也从离体实验层面观察到Re对PDGF-BB所致的VSMCs增殖也具有抑制作用。为进一步探讨其作用机制，我们从在体及离体层面分别发现Re可增加血清或细胞上清NO、eNOS、cGMP含量及血管eNOS表达，意味着Re可激活NO/eNOS/cGMP信号通路，促进血管内皮修复；为进一步观察Re抗增殖的作用机制，我们检测增殖相关标志蛋白，结果发现，Re可通过抑制PCNA、CyclinD1表达及抑制VSMCs表型转化发挥抗增殖作用。本实验进一步研究发现，Re抑制NF-κB活化从而减轻因球囊损伤造成的血管炎性反应在VSMCs增殖过程中也起了重要作用；此外，Re抑制Bcl-2表达，上调Caspase、Bax表达促进VSMC凋亡；对TGF-β1/Ras/ERK1/2 /Smad等信号通路也发挥抑制作用。这为研究阻断AS及RS疾病进展的新药提供重要的理论依据。