靶向VEGF-B的新型异甜菊醇衍生物通过降低氧化应激损伤保护心肌缺血的研究

心肌缺血是严重威胁人类健康的重大疾病，开发新靶点及药物具有重要意义。VEGF-B可以从促进冠脉血管新生，维持线粒体功能等多种途径减轻心肌缺血及再灌注损伤，有望成为全新治疗靶点。最新的研究发现VEGF-B可以降低氧化应激损伤，但此机制是否参与其心肌保护作用尚不清楚。本课题组设计合成了一系列全新异甜菊醇类化合物，通过筛选得到可以激活VEGF-B，且具有显著心肌保护作用的KFH-08。进一步研究发现KFH-08明显提高了抗氧化基因Gpx1的表达。据此，我们提出科学问题：KFH-08是否可通过激活VEGF-B减轻心肌缺血损伤？其机制是否与降低氧化应激损伤有关？本项目将以KFH-08为工具，明确VEGF-B靶向化合物的抗心肌缺血损伤作用；并使用CRISPR/Cas9构建VEGF-B敲除斑马鱼，阐明KFH-08通过VEGF-B保护心肌的分子机制，为未来抗心肌缺血新药研发提供新靶点及理论依据。

Myocardiral ischemia is a major risk worldwide, while novel medicine is still inneed by clinical. VEGF-B perform various bioactivity included pro-angiogenesis, alter energy metabolism and maintance mitochodral function. These activity assumpt VEGF-B to be a potential target for myocardiral ischemia therapy. Resently report indicated that VEGF-B is an antioxidant, though whether the antioxidation was part of the cardiomyoctyte protective effect still need to be proved. We did design and sythsized series of isosteviol analogues. Screening by zebrafish model, we discover one of the novel compound KFH-08 could activity VEGF-B/VEGFR1 signaling and present a significantly cardiomyocyte protected activity. Thus, could KFH-08 attenuates myocardial ischemia injury? and do KFH-08's activity depend on VEGF-B signaling and antioxidation activity have been asked. In this proposal, we will validate the myocardial ischemia protection effect of KFH-08 via targeting VEGF-B; and construct VEGF-B KO zebrafish to investigate the undergo mechenism for KFH-08 induced VEGF-B pathway. This presented study may induce new candidate compound, new medical target and new mechenism for furthur clinical therapy for myocardiral ischemia.