Isosteviol improves cardiac function and promotes angiogenesis after myocardial infarction in rats.
Isosteviol improves cardiac function and promotes angiogenesis after myocardial infarction in rats.
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异甜菊醇可改善大鼠心肌梗塞后的心脏功能并促进血管生成。
DOI：
10.1007/s00441-021-03559-9
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发表时间：
2021
影响因子：
3.6
通讯作者：
Haishan Zhao
中科院分区：
文献类型：
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作者：
Chengbin Zhou;Fei Liu;Laisi Song;Zhiqiang Lu;Tingwei Sun;Jingwen Lun;Xiouou Sun;Wen Tan;Haishan Zhao
异甜菊醇被认为是心肌细胞保护剂。然而，其潜在机制尚不清楚。因此，我们试图在永久性冠状动脉闭塞模型中证实异甜菊醇在心肌梗死后的保护作用，并在体外和体内研究其潜在的促血管生成活性。建立4周永久性冠状动脉闭塞大鼠模型，通过超声心动图和血流动力学评价异甜菊醇的保护作用。采用免疫化学和显微计算机断层扫描（μCT）检测冠状动脉毛细血管密度。研究了异甜菊醇对体外人脐静脉内皮细胞（HUVECs）和体内Tg （kdrl: EGFP）斑马鱼内皮细胞的影响。我们还通过实时聚合酶链反应（RT-qPCR）检测了相关转录因子的表达。异甜菊醇可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）、左室压最大增幅（Max dp/dt）和左室收缩压（LVSP）分别提高32%、40%、25%、26%和10%。有趣的是，它还使冠状动脉毛细血管密度提高了2.5倍。此外，异甜菊醇还能促进体外HUVECs的增殖和分支。它还能促进斑马鱼体内胚胎的节间血管（ISV）发育，并将内皮细胞增殖提高约5倍（4-6）。异甜菊醇还能上调斑马鱼体内缺氧诱导因子-1α (HIF-1α)和血管内皮生长因子A （VEGFA）的表达，分别上调4倍和3.5倍。我们的研究结果表明，异甜菊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。应用永久性冠状动脉闭塞模型，我们证实异甜菊醇能直接促进心肌缺血大鼠血管生成，增加毛细血管密度。异甜菊醇促进斑马鱼体内血管生成，增加HUVECs和斑马鱼血管内皮细胞增殖。异甜菊醇的血管生成活性可能与VEGFA和HIF-1α信号有关。
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.