Abstract
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.
Graphical abstract
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.
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Acknowledgements
We thank Dr. Khaja Shameem Mohammed Abdul and Dr. Shan** Wang for his assistance with the language editing in the manuscript.
Funding
This study was funded by the National Natural Science Foundation of China (Grant No. 81903600 and No.81802123), China Postdoctoral Science Foundation (Grant No. 2018M643026, the Science and Technology Innovation Project of Foshan (Grant No. 2017IT100162), and Technology Major Projects for “Major New Drugs Innovation and Development (2019ZX09301120).
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All procedures performed in the studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee of Guangdong Pharmaceutical University (Approval No. 20180714–03).
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441_2021_3559_MOESM1_ESM.tif
Supplementary file1 Fig. 1 The embryos of wild type and Tg (kdrl: EGFP) zebrafish were used for gating in flow cytometry. (a) The embryos of wild type zebrafish were used as unstained control. P2 was gated based on the population in the unstained control (0.3%, close to 0%). (b) The gating for Tg (kdrl: EGFP) zebrafish groups was determined by referring to the unstained control. The representative image of isosteviol shown that the fluorescent intensity increased (7%) (TIF 1721 KB)
441_2021_3559_MOESM2_ESM.tif
Supplementary file2 Fig. 2 The left ventricular wall thickness and dimension had no significant difference after treatment with isosteviol. (a) Left ventricular end-diastolic posterior wall thickness (LVPW;d) had no significant difference after treatment with isosteviol. n = 8–10 per group. (b) Left ventricular end-systolic posterior wall thickness (LVPW;s) had no significant change after treatment with isosteviol. n = 8–10 per group. (c) Left ventricular end-diastolic internal dimension (LVID;d) had no significant difference after treatment with isosteviol. n = 8–10 per group; (d) Left ventricular end-systolic internal dimension (LVID;s) decreased in the isosteviol group compared with the model group but had no significant difference. #P < 0.05, vs sham group n = 8–10 per group (TIF 3786 KB)
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Supplementary file3 Fig. 3 The energy statue had no significant difference after treatment with isosteviol. (a) Respiratory quotient (RQ) was similar in all groups; (b) Isosteviol moderately rescued EE compared with model group but had no significant difference. n = 8–10 per group (TIF 1964 KB)
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Liu, F., Song, L., Lu, Z. et al. Isosteviol improves cardiac function and promotes angiogenesis after myocardial infarction in rats. Cell Tissue Res 387, 275–285 (2022). https://doi.org/10.1007/s00441-021-03559-9
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DOI: https://doi.org/10.1007/s00441-021-03559-9