NO-姜黄素水凝胶对动脉球囊损伤术后再内皮化的影响及其机制研究

Percutaneous coronary intervention (PCI) has become the major revascularization strategy for the unstable coronary artery disease, but restenosis and delayed endothelialization after the procedure still need to be solved. Endothelial nitric oxide synthase (eNOS) is an important target for promotion to endothelialization and prevention of restenosis after stent implantation. Previously, we had prepared a nitric oxide(NO)-containing hydrogel, which shows the ability to induce endothelial cell migration and promote angiogenesis. Otherwise, curcumin has multiple cardiovascular benefits, such as inflammation regulation, anti-proliferation of vascular smooth muscle cells , protection of vascular endothelial cells. However, the low solubility, poor absorption and low bioavailability hinders its application. Thus, we intend to design a curcumin supramolecular hydrogel which has better water-solubility and higher bioavailability. Combined with our previous research, we aim to develop a NO-curcumin supramolecular hydrogelators (NO-Curcumin-SMHs), which can release NO and curcumin at the carotid artery balloon injury area. Investigating its therapy effects on the smooth muscle cell proliferation, repair and re-endothelialization of endothelial cells, and the underlying mechanism, we expect to offer some new ideas for the prevention and reduction of stent restenosis and late thrombosis.

经皮冠状动脉介入治疗（PCI)已成为不稳定冠状动脉疾病最主要的血运重建策略，但支架术后的再狭窄及延迟内皮化仍需亟待解决。内皮型一氧化氮合酶(eNOS)是促进支架植入后再内皮化并防治再狭窄的重要靶点。我们在前期制备了含NO供体的水凝胶，初步提示具有诱导内皮细胞迁移、促进血管新生的作用。姜黄素具有多重心血管保护作用（调控炎性反应、抗血管平滑肌细胞增殖、保护血管内皮细胞等），但存在难溶于水、吸收差和生物利用度低等弊端，我们又尝试制备出姜黄素水凝胶，可较好地提高水溶性及生物利用度。结合前期研究，我们现拟发展一种可自组装形成含NO供体的姜黄素水凝胶（NO-Curcumin-SMHs），靶向颈动脉球囊损伤部位控制释放NO及姜黄素，共同聚焦其对颈动脉球囊损伤术后血管平滑肌细胞增殖的抑制、内皮细胞的修复及再内皮化的影响,并探讨相关的机制，以期为预防和减少PCI术后支架内再狭窄和晚期血栓的发生提供新思路。

本课题按计划完成了一类载药量高、稳定性好、基于NO供体的新型姜黄素传输体系的构建，能有效减轻或防止冠脉支架植入术后支架内再狭窄和晚期血栓形成的发生风险。体外研究发现，姜黄素-NO水凝胶(Cur-NO-Gel) 可减轻内皮细胞氧化损伤、抑制平滑肌细胞由收缩型向分泌型转化、抑制外膜成纤维细胞向肌成纤维细胞化转化；体内研究发现，姜黄素-NO水凝胶(Cur-NO-Gel) 可以靶向控制释放NO及姜黄素至颈动脉球囊损伤部位，达到促进球囊损伤后血管再内皮化，抑制血管内膜异常增生、血管收缩型重塑的治疗效果。