HIF-1α稳定性在黄芪甲苷促进骨髓间充质干细胞血管新生中的作用机制研究

Treatment of ischemic heart disease by human marrow-derived mesenchymal stem cells (MSCs) is the hot spots on current stem cell research, however, a separate MSCs treatment exists some problems such as: low cell survival rates and no significance in long-term efficacy. Therefore, modification on MSCs is the difficult problem in current researches. Astragaloside Ⅳ is the main active ingredient of Radix Astragali, a traditional Chinese medicine, clinical and basic studies have shown that Astragaloside Ⅳ exerted an effective treatment on ischemic heart disease. Our preliminary study showed that the Astragaloside Ⅳ promoted angiogenesis of MSCs, but its molecular mechanism is unknown. Therefore, based on our previous work, this project aims to evaluate angiogenesis of MSCs promoted by Astragaloside Ⅳ and protective effect against myocardial ischemia in vitro and in vivo experiments. Furthermore, the HIF-1α stabilization is studied to clarify the molecular mechanisms involved in angiogenesis of MSCs promoted by Astragaloside Ⅳ. The launching of this project will help to improve the efficacy of MSCs treatment on ischemic heart disease, it also provide the experimental basis for expanding the scope of clinical application of Traditional Chinese Medicine

骨髓间充质干细胞（MSCs）治疗缺血性心脏病是目前干细胞研究领域的热点，然而单独MSCs治疗存在干细胞存活率低及长期疗效并不显著的问题，因此，对MSCs进行修饰和处理是目前研究的难点问题。黄芪甲苷是我国传统中药黄芪的主要活性成分，临床及基础研究显示黄芪甲苷治疗缺血性心脏病疗效显著。本项目前期研究表明黄芪甲苷具有促进MSCs血管新生的作用，但其分子机制还不明确。因此，在前期工作基础上，本项目拟通过体内体外实验评价黄芪甲苷促进MSCs血管新生的作用及抗心肌缺血的保护作用，并以HIF-1α稳定性作为切入点阐明黄芪甲苷促进MSCs血管新生的分子机制。本项目的开展不仅有利于提高MSCs治疗缺血性心脏病的疗效，而且能为扩大传统中药的临床应用范围提供实验依据。

骨髓间充质干细胞（MSCs）移植修复梗死心肌已成为研究的热点。但在缺氧环境中MSCs存活率低，细胞移植后心肌修复效果不显著，因此提高MSCs移植疗效至关重要。本项目通过体内体外实验评价黄芪甲苷促进MSCs血管新生作用及抗心肌缺血的保护作用，并以HIF-1α稳定性为切入口阐明黄芪甲苷促进MSCs血管新生的分子机制。本项目研究工作证实1）黄芪甲苷与MSCs联合应用通过促进血管新生改善心梗大鼠的心功能及恢复下肢缺血大鼠的血流供应；2）黄芪甲苷通过提高HIF-1α稳定性促进其下游促血管新生因子VEGF的蛋白表达及分泌从而诱导血管新生；3）黄芪甲苷通过PI3K/AKT通路抑制HIF-1α的降解从而提高HIF-1α的稳定性，促进其蛋白表达增加。本项目的研究成果不仅能提高干细胞移植治疗的效果，而且有助于扩大传统中药的临床应用范围。