School of Biomedical Pharmaceutical Science, Guangdong University of Technology, Guangzhou, 510006, Guangdong, China.
Hengqin New Area, Zhuhai Yuanzhi Health Technology Co. Ltd, Zhuhai, 519000, Guangdong, China.
Cell Tissue Res. 2022 Feb;387(2):275-285. doi: 10.1007/s00441-021-03559-9. Epub 2021 Nov 25.
Isosteviol has been indicated as a cardiomyocyte protector. However, the underlying mechanism remains unclear. Thus, we sought to confirm the protective effect of isosteviol after myocardial infarction in a model of permanent coronary artery occlusion and investigate the potential proangiogenic activity in vitro and in vivo. A 4-week permanent coronary artery occlusion rat model was generated, and the protective effect of isosteviol was evaluated by echocardiographic imaging and hemodynamics assays. The coronary capillary density was tested by immunochemistry and micro-computed tomography (μCT) imaging. The effect of isosteviol on endothelial cells was determined in human umbilical vein endothelial cells (HUVECs) in vitro and Tg (kdrl: EGFP) zebrafish in vivo. We also examined the expression of related transcription factors by real-time polymerase chain reaction (RT-qPCR). Isosteviol increased ejection fraction (EF), fractional shortening (FS), cardiac systolic index (CI), maximum rate of increase of left ventricular pressure (Max dp/dt), and left ventricular systolic pressure (LVSP) by 32%, 40%, 25%, 26%, and 10%, respectively, in permanent coronary artery occlusion rats. Interestingly, it also promoted coronary capillary density by 2.5-fold. In addition, isosteviol promoted the proliferation and branching of HUVECs in vitro. It also rescued intersegmental vessel (ISV) development and improved endothelial cell proliferation by approximately fivefold (4-6) in zebrafish embryos in vivo. Isosteviol also upregulated the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) in zebrafish by fourfold and 3.5-fold, respectively. Our findings suggest that isosteviol is a proangiogenic agent and that this activity is related to its protective effects against myocardial ischemia. After using the permanent coronary artery occlusion model, we demonstrated that isosteviol promotes angiogenesis directly and increases capillary density in myocardial ischemia rats. Isosteviol promotes angiogenesis in zebrafish in vivo and increases vascular endothelial cell proliferation in HUVECs and zebrafish. The angiogenesis activity of isosteviol may be correlated with VEGFA and HIF-1α signaling.
异甜醇已被证实具有心肌细胞保护作用。然而，其潜在机制尚不清楚。因此，我们旨在通过永久性冠状动脉闭塞模型证实异甜醇对心肌梗死的保护作用，并研究其潜在的促血管生成活性。建立了 4 周永久性冠状动脉闭塞大鼠模型，通过超声心动图成像和血液动力学检测评估异甜醇的保护作用。通过免疫化学和微计算机断层扫描（μCT）成像检测冠状动脉毛细血管密度。在人脐静脉内皮细胞（HUVEC）体外和 Tg（kdrl：EGFP）斑马鱼体内研究异甜醇对内皮细胞的作用。我们还通过实时聚合酶链反应（RT-qPCR）检测相关转录因子的表达。异甜醇使永久性冠状动脉闭塞大鼠的射血分数（EF）、缩短分数（FS）、心脏收缩指数（CI）、左心室压力最大上升率（Max dp/dt）和左心室收缩压（LVSP）分别增加 32%、40%、25%、26%和 10%。有趣的是，它还使冠状动脉毛细血管密度增加了 2.5 倍。此外，异甜醇促进了 HUVEC 的体外增殖和分支。它还挽救了节段间血管（ISV）的发育，并使斑马鱼胚胎内皮细胞的增殖增加了约五倍（4-6 倍）。异甜醇还使斑马鱼中的缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子 A（VEGFA）的表达分别增加了 4 倍和 3.5 倍。我们的研究结果表明，异甜醇是一种促血管生成剂，这种活性与其对心肌缺血的保护作用有关。在使用永久性冠状动脉闭塞模型后，我们证明异甜醇直接促进血管生成，并增加心肌缺血大鼠的毛细血管密度。异甜醇在体内促进斑马鱼的血管生成，并增加 HUVEC 和斑马鱼中的血管内皮细胞增殖。异甜醇的血管生成活性可能与 VEGFA 和 HIF-1α信号有关。
