阿魏酸乙酯通过抑制转化生长因子受体1来抑制心肌梗死后的心肌纤维化。
Ethyl ferulate suppresses post-myocardial infarction myocardial fibrosis by inhibiting transforming growth factor receptor 1.
作者信息
Zeng Ke-Feng, Wang Hui-Juan, Deng Bo, Chen Ting-Fang, Chen Jun-Bang, Ding Wen-Jun, Chen Si, Xie Jun-di, Lu Si-Min, Chen Guang-Hong, Zhang Ying, Tan Zhang-Bin, Ou Hong-Bin, Tan Yong-Zhen, Zhang Shuang-Wei, Zhou Ying-Chun, Zhang Jing-Zhi, Liu Bin
机构信息
Department of Traditional Chinese Medicine, Guangzhou Institute of Cardiovascular Disease, State Key Laboratory of Respiratory Disease, Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, the Second Affiliated Hospital of Guangzhou Medical University, 250 Changgangdong Road, Guangzhou 510260, China.
School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou 510515, China.
出版信息
Phytomedicine. 2023 Dec;121:155118. doi: 10.1016/j.phymed.2023.155118. Epub 2023 Sep 23.
BACKGROUND
With an increasing number of myocardial infarction (MI) patients, myocardial fibrosis is becoming a widespread health concern. It's becoming more and more urgent to conduct additional research and investigations into efficient treatments. Ethyl ferulate (EF) is a naturally occurring substance with cardioprotective properties. However, the extent of its impact and the underlying mechanism of its treatment for myocardial fibrosis after MI remain unknown.
PURPOSE
The goal of this study was to look into how EF affected the signaling of the TGF-receptor 1 (TGFBR1) in myocardial fibrosis after MI.
METHODS
Echocardiography, hematoxylin-eosin (HE) and Masson trichrome staining were employed to assess the impact of EF on heart structure and function in MI-affected mice in vivo. Cell proliferation assay (MTS), 5-Ethynyl-2'-deoxyuridine (EdU), and western blot techniques were employed to examine the influence of EF on native cardiac fibroblast (CFs) proliferation and collagen deposition. Molecular simulation and surface plasmon resonance imaging (SPRi) were utilized to explore TGFBR1 and EF interaction. Cardiac-specific Tgfbr1 knockout mice (Tgfbr1) were utilized to testify to the impact of EF.
RESULTS
In vivo experiments revealed that EF alleviated myocardial fibrosis, improved cardiac dysfunction after MI and downregulated the TGFBR1 signaling in a dose-dependent manner. Moreover, in vitro experiments revealed that EF significantly inhibited CFs proliferation, collagen deposition and TGFBR1 signaling followed by TGF-β1 stimulation. More specifically, molecular simulation, molecular dynamics, and SPRi collectively showed that EF directly targeted TGFBR1. Lastly, knocking down of Tgfbr1 partially reversed the inhibitory activity of EF on myocardial fibrosis in MI mice.
CONCLUSION
EF attenuated myocardial fibrosis post-MI by directly suppressing TGFBR1 and its downstream signaling pathway.
背景
随着心肌梗死（MI）患者数量的增加，心肌纤维化正成为一个广泛关注的健康问题。开展更多关于有效治疗方法的研究和调查变得越来越迫切。阿魏酸乙酯（EF）是一种具有心脏保护特性的天然物质。然而，其对MI后心肌纤维化的影响程度及其治疗的潜在机制仍不清楚。
目的
本研究的目的是探讨EF对MI后心肌纤维化中转化生长因子受体1（TGFBR1）信号传导的影响。
方法
采用超声心动图、苏木精-伊红（HE）染色和Masson三色染色评估EF对体内MI小鼠心脏结构和功能的影响。采用细胞增殖测定（MTS）、5-乙炔基-2'-脱氧尿苷（EdU）和蛋白质印迹技术检测EF对原代心脏成纤维细胞（CFs）增殖和胶原沉积的影响。利用分子模拟和表面等离子体共振成像（SPRi）探索TGFBR1与EF的相互作用。利用心脏特异性Tgfbr1基因敲除小鼠（Tgfbr1）验证EF的作用。
结果
体内实验表明，EF可减轻心肌纤维化，改善MI后的心脏功能障碍，并以剂量依赖性方式下调TGFBR1信号传导。此外，体外实验表明，EF可显著抑制CFs增殖、胶原沉积和TGF-β1刺激后的TGFBR1信号传导。更具体地说，分子模拟、分子动力学和SPRi共同表明EF直接作用于TGFBR1。最后，敲低Tgfbr1部分逆转了EF对MI小鼠心肌纤维化的抑制活性。
结论
EF通过直接抑制TGFBR1及其下游信号通路减轻MI后的心肌纤维化。
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