活血化瘀抗动脉粥样硬化与血栓形成的剪应力效应机理

Recently, we developed a new borderline discipline-biomechanopharmacology for pharmacology of Chinese medicine. The concept was introduced in the well-known journal--Trends in Pharmacological Sciences (IF: 13.6 in 2006). The article then attracted attention internationally. The hypothesis of the project is the follows: Low shear stress (SS) in blood vessel is a common feature in blood stasis syndrome in Chinese medicine, and one of the intension of the therapeutic principle of activating blood circulation to remove blood stasis (ABCRBS) is to elevate shear stress appropriately. Therefore, the functions of endothelial cells are regulated by the elevated SS, and the preventive and therapeutic effects could be gained for intervention of atherosclerosis (AS) and thrombosis. The project focuses on the interactions among endothelial cells, blood SS and blood. The project consists of three categories of research: Firstly, the dose-response between the factors secreted by endothelial cells related to atherosclerosis, thrombosis and thrombolysis and the multi-levels of full range physiological shear stress. Secondly, the responses of the ex vivo vessel segment under different SS will be explored as a continuation of the first. Based on the factorial design, the joint application of a popular pair of ABCRBS herbs, Salvia miltiorrhiza and Crataegus Pinnatifida, with the measure of elevating shear stress (exercise) will be investigated for prevention and treatment of AS. Animal experiment of AS model combined with thrombosis and injury models in vitro and ex vivo of endothelial cells will be used. Parameters in lipid metabolism, inflammatory factors, anti-oxidation etc will be monitored. Thirdly, animal models of AS and thrombosis will be employed to investigate the effects of non-drug ABCRBS (exercise) and the herbal pair of ABCRBS (Salvia miltiorrhiza +Crataegus Pinnatifida) individually and jointly. The project focuses on the biomechanopharmacological mechanism and new approach in intervention of AS and thrombosis, and the development of the pharmacology of Chinese material medica.

课题组近年基于中药药理研究,开拓了一门新的交叉学科--生物力药理学,并在国际药理学权威刊物Trends Pharmaco Sci（2006年IF:13.6）发表,引起国际高度关注。本标书假说如下:从生物效应考虑,血流剪应力可等效为药物,具有确切的调节血管内皮细胞多方面功能的量-效关系,可干预与防治AS及血栓形成等病变。血流剪应力低下是血瘀证的共性特征,适度提高血流剪应力是活血化瘀的重要科学内涵之一。本课题从血管内皮细胞/血流剪应力/血液相互作用入手,进行三个层次的实验研究:一、全程生理剪应力对血管内皮细胞AS、血栓形成及血栓溶解有关因子的剂量-效应关系；二、在离体血管对于细胞层次的结果做进一步研究;三、在整体动物AS与血栓形成模型上研究非药物活血化瘀(运动)与活血化瘀药对(丹参+山楂)的分别贡献与联合效应。本项目探讨活血化瘀防治AS与血栓形成的新途径与机制,并以边缘学科促进中药药理学发展。

动脉粥样硬化（AS）及血栓形成导致的心脑血管疾病是危害人类健康的主要疾病，其发病率和病死率均居各类疾病的首位。包括血流剪应力在内的生物力学因素在AS及动脉血栓形成过程中起到重要的作用。本研究将血流剪应力与活血化瘀药物联合应用，探讨其联合作用对AS及血栓形成的作用机制，从血管内皮细胞、离体血管段、整体动物模型这三个层次进行实验研究。通过研究发现，剪应力与丹参山楂提取物可以通过调节HUVECs细胞中纤溶系统的稳定性来抑制血栓形成；剪应力和压力联合应用以复杂的非线性方式影响了离体血管段中PAI-1、t-PA、vWF的分泌及基因的表达，并使离体血管段剪切液中NO/ET和t-PA/PAI-1的比值增大，有利于血管的舒张和血栓的溶解，改善内皮细胞功能，达到延缓AS进程的作用；血流剪应力能降低AS大鼠体内血脂水平及炎症因子的分泌，调节内皮细胞分泌功能，改善大鼠AS斑块的脂质沉积，提示其具有药物般的生物效应，具有防治AS 与血栓形成的潜力；丹参山楂提取物配伍和定量运动（自身调节血流剪应力）能够调控PAI-1、t-PA、COX-1和 vWF等相关基因表达，保护血管内皮细胞功能达到抗动脉粥样硬化的作用；运动联合丹参山楂提取物能够减少光化学诱导的局灶性脑梗塞大鼠梗死灶面积，并通过调节纤溶系统的稳定性、调控6-keto-PGF1α /TXB2的平衡来抑制血栓形成，抑制ICAM-1和VCAM-1等粘附分子蛋白的表达,减轻炎症反应，抑制VWF蛋白表达并减少其分泌，保护内皮细胞功能并减少血小板黏附和聚集来抑制血栓形成。本研究通过将血流剪应力与活血化瘀中药联合应用，从多层面多途径探讨了活血化瘀防治动脉粥样硬化及血栓形成的新途径及作用机理，并以边缘学科生物力药理学促进中药药理学的发展。