Myocardial protective effect and transcriptome profiling of Naoxintong on cardiomyopathy in zebrafish

Abstract

Background 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. Methods 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. Results 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. Conclusion NXT presented myocardial protective effect and could restore myocardial injury and cardiac dysfunction in zebrafish; the action mechanism was involved in HEG1-CCM signaling.

Nile Tilapia (Oreochromis niloticus) Patched1 Mutations Disrupt Cardiovascular Development and Vascular Integrity through Smoothened Signaling

“…Multiple factors such as cardiac pumping insufficiency, chamber myocardial injury and chamber looping defect, alterations of ion channels and osmotic imbalance of body fluids may contribute to the phenotype of pericardial and yolk sac edema. In zebrafish, reports have shown abnormalities in the development and function of the heart or arteries, such as cardiac pumping insufficiency with atrial blood cell accumulation [ 36 ] and developmental defects of the aortic arch [ 37 ], leading to pericardial edema. There is a phenotype of elongated heart and cavity ring defects in zebrafish heartstrings ( hst ) mutants, where the T-box domain encoding the Tbx5 transcription factor is located in the hst gene [ 38 ].…”

Membranous Expression of Heart Development Protein with EGF-like Domain 1 Is Associated with a Good Prognosis in Patients with Bladder Cancer

“…HEG1 protein directly connects with and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial cell junctions to regulate and maintain the organization of junctional molecules, which are critical for vertebrate cardiovascular development [22][23][24]. Other functions of the HEG1 protein such as angiogenesis [8,9], cell-cell junction [10], embryonic development [11,12], and cell proliferation [13] are gradually becoming clear. Kreuk et al investigated Ras-interacting protein 1 (RASIP1), a membranous protein that is also essential for cardiovascular development.…”

“…Heart development protein with EGF-like domain 1 (HEG1) was discovered during the study of a zebrafish heart [7] and is expressed in different tissues involved in various physiological processes such as angiogenesis [8,9], cell-cell junction [10], embryonic development [11,12], and cell proliferation [13] These processes are associated with tumor development and progression, suggesting that HEG1 may play a crucial role in cancer development. Sialylated HEG1 is prominently expressed in many mesothelioma cases, demonstrating its potential as a valuable marker for the differential diagnosis of mesothelioma due to its high specificity [13][14][15][16][17][18].…”

Bacterial Quorum-Sensing Signal DSF Inhibits LPS-Induced Inflammations by Suppressing Toll-like Receptor Signaling and Preventing Lysosome-Mediated Apoptosis in Zebrafish

“…The false discovery rate (FDR) was used to correct the p value to determine the true DEGs. For analyzing the gene expression difference between two samples, p value < 0.05 and|log2(Fold change)| ≥ 1 were considered significant DEGs and used for further analysis [67].…”