丹红注射液对小鼠移植心脏冷保存损伤的保护作用及配伍增效机制研究

Extending the safe period of cold preservation and reducing the damage of donor organs have been recognized as big challenges in organ transplantation. The role of traditional Chinese medicine in the protection of cold preservation injury of transplanted heart was rarely studied. Danhong Injection (DI), a Chinese medical product extracted from Chinese herbs Danshen and Honghua, has been widely used to treat heart disease caused by ischemia and hypoxia. According to previous study, the applicants found adding DI reduced injury and extended preservation time of mice transplanted hearts during cold preservation. The water-soluble salvianolic acid B, lipid soluble salvianone IIA in Danshen and hydroxyl safflower A in safflower had significant protective effects on myocardial injury when they used alone. This project intends to systematically study the protective mechanism of the three representative compounds mentioned above in DI. Based on the regulatory effects of three compounds on three programmed death of myocardial cells, including autophagy (salvianolic acid B), apoptosis (tanshinone IIA), and ferroptosis (hydroxyl safflower A) induced by ischemia and hypoxia, this study aimed to investigate the compatibility synergistic effect and the molecular mechanism of DI on myocardial injury protection in cold preservation of mouse transplanted hearts. This research will provide a scientific basis for the application of DI in cold preservation of transplanted hearts.

如何延长供体心脏冷保存时间，减轻心肌组织损伤是心脏移植成功的关键，也是器官移植领域的难题。中药在移植心脏冷保存损伤保护中的作用研究极少。丹红注射液作为活血化瘀中药丹参与红花的复方制剂，临床上广泛用于缺血缺氧引起的心脏疾病。申请者前期研究发现器官冷保存液中加入丹红注射液可有效减轻小鼠移植心脏冷保存损伤并延长心脏冷保存时间；丹参水溶性化合物丹酚酸B、脂溶性化合物丹参酮IIA以及红花中羟基红花黄素A单独使用均有显著的心肌损伤保护作用。本项目拟在此基础上对丹红注射液上述三种代表性化合物的损伤保护机制进行系统研究，基于三种化合物对缺血缺氧引起的自噬（丹酚酸B）、凋亡（丹参酮IIA）、铁死亡（羟基红花黄素A）三种心肌细胞程序性死亡机制的调控作用，深入研究丹红注射液对小鼠移植心脏冷保存心肌损伤保护的配伍增效作用及分子机制，为丹红注射液应用于移植心脏冷保存提供科学依据。

器官保存领域的最新进展主要体现在保存液的改进和保存技术的发展。静态低温保存技术（cold storage，CS）是目前临床应用最广泛的器官保存方式。CS利用低温器官保存液置换供体器官中的血液，使器官在低温下维持较低的新陈代谢水平，并增加器官对缺血、缺氧的耐受性，可离体保存较长时间。但因为部分器官在UW液灌洗保存后发生功能不全，引起较高的缺血型胆道损坏发生率，且其成分复杂且价格昂贵等限制了它在国内更加广泛的运用。近年来研究发现，许多中药对器官保存中组织缺血损伤有较好的保护作用，我国学者在从中药中筛选高效低毒的药物加入保存液中，以降低器官在保存液中的损害。.对丹参代表性化合物丹酚酸B的心保护作用进行验证，采用现代生物学手段从整体动物水平开展丹参化合物对自噬和凋亡的调控作用研究，阐明了丹酚酸B心保护效应与介导自噬与凋亡之间的关系。.开展红花化合物对冷保存小鼠心脏的干预作用研究，用现代生物学手段从整体动物水平开展红花化合物的心保护作用，证明了红花可以通过调控PI3K-AKT信号通路产生保护作用