Hu Mengyan, Liu Peirong, Lu Shuxian, Wang Zhihao, Lyu Zhaojie, Liu Hongkai, Sun Yuhong, Liu Feng, Tian Jing
Western China Zebrafish Research Center for Human Diseases and Drug Screening, The College of Life Sciences, Northwest University, Xi'an, 710069, China.
Shaanxi Buchang Pharmaceutical Co. Ltd., Xi'an, 710075, China.
Chin Med. 2021 Nov 14;16(1):119. doi: 10.1186/s13020-021-00532-0.
Cardiomyopathy is a kind of cardiovascular diseases, which makes it more difficult for the heart to pump blood to other parts of the body, eventually leading to heart failure. Naoxintong (NXT), as a traditional Chinese Medicine (TCM) preparation, is widely used in the treatment of cardiovascular diseases, including cardiomyopathy, while its underlying mechanism has not been fully elucidated. The purpose of this study is to investigate the therapeutic effect of NXT on cardiomyopathy and its molecular mechanism in zebrafish model.
The zebrafish cardiomyopathy model was established using terfenadine (TFD) and treated with NXT. The therapeutic effect of NXT on cardiomyopathy was evaluated by measuring the heart rate, the distance between the sinus venosus and bulbus arteriosus (SV-BA), the pericardial area, and the blood flow velocity of zebrafish. Then, the zebrafish hearts were isolated and collected; transcriptome analysis of NXT on cardiomyopathy was investigated. Moreover, the heg1 mutant of zebrafish congenital cardiomyopathy model was used to further validate the therapeutic effect of NXT on cardiomyopathy. Additionally, UPLC analysis combined with the zebrafish model investigation was performed to identify the bioactive components of NXT.
In the TFD-induced zebrafish cardiomyopathy model, NXT treatment could significantly restore the cardiovascular malformations caused by cardiac dysfunction. Transcriptome and bioinformatics analyses of the TFD and TFD + NXT treated zebrafish developing hearts revealed that the differentially expressed genes were highly enriched in biological processes such as cardiac muscle contraction and heart development. As a cardiac development protein associated with cardiomyopathy, HEG1 had been identified as one of the important targets of NXT in the treatment of cardiomyopathy. The cardiovascular abnormalities of zebrafish heg1 mutant could be recovered significantly from NXT treatment, including the expanded atrial cavity and blood stagnation. qRT-PCR analysis further showed that NXT could restore cardiomyopathy phenotype in zebrafish through HEG1-CCM signaling. Among the seven components identified in NXT, paeoniflorin (PF) and salvianolic acid B (Sal B) were considered to be the main bioactive ones with myocardial protection.
NXT presented myocardial protective effect and could restore myocardial injury and cardiac dysfunction in zebrafish; the action mechanism was involved in HEG1-CCM signaling.
心肌病是一种心血管疾病，会使心脏向身体其他部位泵血变得更加困难，最终导致心力衰竭。脑心通（NXT）作为一种中药制剂，广泛用于治疗包括心肌病在内的心血管疾病，但其潜在机制尚未完全阐明。本研究的目的是在斑马鱼模型中研究NXT对心肌病的治疗作用及其分子机制。
使用特非那定（TFD）建立斑马鱼心肌病模型并用NXT进行治疗。通过测量斑马鱼的心率、静脉窦与动脉球之间的距离（SV-BA）、心包面积和血流速度来评估NXT对心肌病的治疗效果。然后，分离并收集斑马鱼心脏；研究NXT对心肌病的转录组分析。此外，使用斑马鱼先天性心肌病模型的heg1突变体进一步验证NXT对心肌病的治疗效果。另外，进行超高效液相色谱（UPLC）分析并结合斑马鱼模型研究以鉴定NXT的生物活性成分。
在TFD诱导的斑马鱼心肌病模型中，NXT治疗可显著恢复由心脏功能障碍引起的心血管畸形。对TFD和TFD + NXT处理的斑马鱼发育中心脏的转录组和生物信息学分析表明，差异表达基因在心肌收缩和心脏发育等生物学过程中高度富集。作为与心肌病相关的心脏发育蛋白，HEG1已被确定为NXT治疗心肌病的重要靶点之一。斑马鱼heg1突变体的心血管异常可通过NXT治疗得到显著恢复，包括心房腔扩大和血液停滞。qRT-PCR分析进一步表明，NXT可通过HEG1-CCM信号通路恢复斑马鱼的心肌病表型。在NXT鉴定出的七种成分中，芍药苷（PF）和丹酚酸B（Sal B）被认为是具有心肌保护作用的主要生物活性成分。
NXT具有心肌保护作用，可恢复斑马鱼的心肌损伤和心脏功能障碍；其作用机制涉及HEG1-CCM信号通路。
