基于Nrf2/HO-1通路探讨双丹方促心肌缺血后血管新生作用的药效物质基础及分子机制

Coronary heart disease (CHD), which has another name called asischemic heart disease (IHD), is one of the world’s most threatening diseases. Therapeutic angiogenesis is an important strategy for the recovery after myocardial ischemia injury, which is complementary to the “Eliminating blood stasis and promoting tissue regeneration” theory in traditional Chinese medicine. ShuangDan prescription (SD), composed of two traditional Chinese medicinal herbs (Cortex Moutan and Radix Salvia Miltiorrhizae), has been effectively used for the treatment of angina pectoris, myocardial infarction and other CHD symptoms in clinical practice. Our previous studies had demonstrated that SD as well as its ingredients could significantly ameliorate infarct volume, inhibit apoptosis and enhance the antioxidant defense system through activating of Nrf2/HO-1 signaling. Nrf2/HO-1 is a new regulation pathway in vascular endothelial growth factor (VEGF)-induced angiogenesis. Our preliminary experiment indicated that SD could promote the angiogenesis of chicken chorioallantoic membrane as well as increase protein expression of VEGF and CD34 in myocardium after myocardial infarction. Whether the material base of SD could improve angiogenesis to protect myocardial ischemia injury through regulation of Nrf2/HO-1 are needed further studies. This study planned to screen active compounds of SD and study the myocardial protection of these active components through promoting angiogenesis on the animal, cellular and molecular levels. Our study will provide a new strategy for clinical treatment of CHD.

缺血性心脏病是严重危害人类健康的重大疾病，促血管新生治疗在心肌缺血损伤预后中发挥重要作用，这与中医治疗冠心病的“祛瘀生新”理论有异曲同工之妙。双丹方由丹参、牡丹皮两味中药组成，为活血化瘀的经典复方，其系列制剂长期应用于冠心病的临床实践，取得了良好的疗效。我们前期研究证实，双丹方有效成分能够通过调控Nrf2/HO-1通路降低实验动物心梗面积、组织氧化损伤水平及细胞凋亡水平，发挥心肌保护作用。有研究表明，Nrf2/HO-1是介导新生血管形成的潜在靶点。我们的预实验也发现，双丹方能够促鸡胚绒毛尿囊膜血管生成、提高心梗大鼠心肌VEGF及CD34蛋白表达，有潜在促血管新生作用。然而，双丹方是否通过调控Nrf2/HO-1通路进而促进血管新生发挥抗心肌缺血损伤作用，尚待验证。本课题拟在筛选出双丹方促血管新生药效物质的基础上，阐明其促血管新生保护缺血心肌的作用机制，为冠心病临床药物治疗提供新的思路。

缺血性心脏病是严重危害人类健康的重大疾病，促血管新生治疗在心肌缺血损伤预后中发挥重要作用，近年来的大量研究表明，Nrf2/HO-1是介导新生血管形成的潜在靶点。双丹方是由丹参、牡丹皮两味中药组成的活血化瘀经典复方，临床用于治疗冠心病心绞痛，效果良好。双丹方是否通过调控Nrf2/HO-1通路进而促进血管新生发挥抗心肌缺血损伤作用，尚待验证。本项目建立了在体大鼠心肌缺血损伤模型、体外缺氧诱导的的心肌微血管内皮细胞损伤模型，通过确证双丹方的促血管新生作用、筛选其药效物质、揭示药效物质作用机制等研究，探索了双丹方的促血管新生作用及其药效物质的作用机制。项目研究结果证实了双丹方的促血管生成作用，并初步筛选出5个具有潜在促血管新生作用的药效物质，同时揭示了药效物质之一没食子酸的可能作用机制，暨没食子酸可以通过调控Nrf2/HO-1通路促血管新生而发挥心肌保护作用。本项目的完成为双丹方配伍作用的原理与科学合理性提供了实验依据，为冠心病临床药物治疗提供了新的思路。