丹参素抗血小板聚集和保护内皮细胞作用靶点的研究

Platelet aggregation and endothelial cell injury are important triggers in the development of cardiovsaxular diseases (CVDs). Many years ago, Danshensu (DSS), one active hydrophilic compound of many traditional Chinese medicinal formulas, such as Danshen dripping pill and Danshen injection, was used to treat CVDs in China, the exact mechanism of its action is unknown. Today, DSS is more widely used as a therapeutic reagent for CVDs, although how it execute its biological activity still remains to be fully characterized. Here, we identified for the first time that DSS directly targeted ERp57 (endoplasmic reticulum protein 57) among platelet proteins and inhibited the activity of ERp57. Previous studies reported that ERp57 plays a critical role in regulation of platelet aggregation and thrombus formation, and its inhibitors may present novel class of antithrombotic agents. Our current study may reveal a new mechanism for the therapeutic effects conferred by DSS on CVDs. The targets and underlying mechanism will be further investigated on platelet aggregation, endothelial cell damage-induced by oxidative stress and zebrafish vessel loss-induced by VEGF kinase inhibitor based on the previous novel results to try to answer the following scientific questions: ① Identify the signaling pathways downstream of ERp57 that are mediated by DSS to inhibit platelet aggregation in vitro. ② Explore whether other proteins are interacted with DSS on endothelial cells and zebrafish using chemical proteomic approach, and the related signaling pathways are involved in the vascular protective effects conferred by DSS. So far, there are no other similar reports regarding the interaction between DSS and ERp57, and it deserved to be explored on the different cardiovascular models. This study has the potential to characterize the benefical mechanism conferred by DSS on platelate aggregation and edothelial cell injury. In addition, these scientific findings of interaction between DSS and the proteins also provide new rationales and ideas for target discovery of ancient Chinese herbal formula and the development of small molecule probes and drugs at ERp57 for anti-thrombotic therapy and clinical cardiovascular disorders.

血小板聚集和内皮细胞损伤，与心血管疾病的发生密切相关。以丹参素为主要成分的复方中药，如复方丹参滴丸，广泛用于治疗心肌梗塞等心血管病，效果显著，但其作用靶点尚不清楚。我们前期利用化学蛋白质组学的方法首次发现丹参素与血小板ERp57（内质网蛋白57）蛋白结合，并抑制其活性。丹参素对ERp57蛋白及其下游信号通路的调控，可能是丹参素对抗心血管病的新机制。本课题在前期创新性结果的基础上，拟采用血小板聚集、内皮细胞氧化损伤和斑马鱼血管损伤三种病理模型对丹参素心血管相关的保护作用靶点及其机制进行深入探讨，将完成以下研究：① 在血小板聚集模型，丹参素对ERp57下游信号通路的调控。② 在内皮细胞和斑马鱼模型， 丹参素是否存在其它作用靶点，实现对内皮细胞和血管的保护作用。该项目的实施为丹参素对血小板聚集和内皮细胞保护作用的药物靶点给予解释，并为中药靶点的解析及新药的设计和开发提供研究基础。

血小板聚集和内皮细胞损伤，与心血管疾病的发生密切相关。以丹参素为主要成分的复方中药，如复方丹参滴丸，广泛用于治疗心肌梗塞等心血管病，效果显著，但其作用靶点尚不清楚。我们前期利用化学蛋白质组学的方法首次发现丹参素与血小板ERp57（内质网蛋白57）蛋白结合，并抑制其活性。丹参素对ERp57蛋白及其下游信号通路的调控，可能是丹参素对抗心血管病的新机制。本课题在前期创新性结果的基础上，拟采用血小板聚集、内皮细胞氧化损伤和斑马鱼血管损伤三种病理模型对丹参素心血管相关的保护作用靶点及其机制进行深入探讨，将完成以下研究：① 在血小板聚集模型，丹参素对ERp57下游信号通路的调控。② 在内皮细胞和斑马鱼模型， 丹参素是否存在其它作用靶点，实现对内皮细胞和血管的保护作用。该项目的实施为丹参素对血小板聚集和内皮细胞保护作用的药物靶点给予解释，并为中药靶点的解析及新药的设计和开发提供研究基础。