[Bioinformatics and animal experiments reveal mechanism of Linggui Zhugan Decoction in ameliorating chronic heart failure after myocardial infarction via HIF-1α/HO-1 signaling pathway].

Q3 Pharmacology, Toxicology and Pharmaceutics
Han Ren, Shu-Shu Wang, Wan-Zhu Zhao, Shao-Hua Xu, Ke-Dong Wei, Wan-Wan Wu, Sheng-Yi Huang, Rui Cai, Yuan-Hong Zhang, Jin-Ling Huang
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引用次数: 0

Abstract

This study aims to investigate the effect of Linggui Zhugan Decoction(LGZGD) on autophagy in the mouse model of chronic heart failure(CHF) induced by myocardial infarction(MI), as well as the regulatory effect of LGZGD on the hypoxia-inducible factor-1α(HIF-1α)/heme oxygenase-1(HO-1) signaling pathway, based on bioinformatics and animal experiments. The active ingredients and corresponding targets of LGZGD were retrieved from the Traditional Chinese Medicine Systems Pharmacology and Analysis Database, and GEO, GeneCards, and DisGeNET were searched for the disease targets. Cytoscape was used to establish a "drug-component-target" network. The protein-protein interaction(PPI) network analysis was performed on STRING. R language was used for Gene Ontology(GO) and Kyoto Encycloperfia of Genes and Genomes(KEGG) enrichment analyses. Molecular docking was adopted to validate the core targets. The mouse model of MI-induced CHF was established by surgical ligation of the left anterior descending coronary artery. The modeled mice were assigned into the sham, model, low-, medium-, and high-dose(2.34, 4.68, and 9.36 g·kg~(-1), respectively) LGZGD, and captopril(3.25 mg·kg~(-1)) groups. After continuous administration for 6 weeks, a Doppler ultrasound imaging system was used to examine the heart function indicators: left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), left ventricular end-systolic dimension(LVIDs), and left ventricular end-diastolic dimension(LVIDd). The myocardial tissue was stained with hematoxylin-eosin for the observation of morphological changes. The mRNA levels of microtubule-associated protein 1 light chain 3 beta(LC3B), Beclin1, p62, HIF-1α, and HO-1 in the myocardial tissue were determined by RT-qPCR. The protein levels of LC3B, beclin1, p62, autophagy-related protein 5(ATG5), HIF-1α, and HO-1 were determined by Western blot. The results showed that 103 active components of LGZGD, corresponding to 224 targets, were obtained. A total of 3 485 and 6 165 targets related to MI and CHF, respectively, were retrieved. The GSE16499 dataset obtained 3 263 differentially expressed genes. There were 31 common targets. The top 3 core active components were quercetin, naringenin, and 1-methoxyphaseollidin. The topology analysis results showed that the core targets were MAPK3, HMOX1(HO-1), MYC, ADRB2, PPARD, and HIF1A(HIF-1α). The molecular docking results showed strong binding between the core targets and the main active components of LGZGD. LGZGD significantly improved the heart function and alleviated the pathological changes in the myocardial tissue of mice. Western blot and RT-qPCR results showed that the HIF-1α/HO-1 signaling pathway and autophagy were activated in the model group. LGZGD up-regulated the levels of LC3B, Beclin1, ATG5, HIF-1α, and HO-1 while down-regulating the mRNA and protein levels of p62. In summary, LGZGD can enhance autophagy and improve the heart function in the mouse model of CHF after MI by upregulating the HIF-1α/HO-1 signaling pathway.

[生物信息学和动物实验揭示灵归柱肝汤通过HIF-1α/HO-1信号通路改善心肌梗死后慢性心力衰竭的机制]。
本研究旨在基于生物信息学和动物实验,探讨灵归助肝汤(LGZGD)对心肌梗死(MI)慢性心力衰竭(CHF)小鼠模型自噬的影响,以及灵归助肝汤对缺氧诱导因子-1α(HIF-1α)/血红素加氧酶-1(HO-1)信号通路的调控作用。从中国中药系统药理学与分析数据库中检索LGZGD的有效成分及相应靶点,并在GEO、GeneCards和DisGeNET中检索其疾病靶点。利用细胞图建立“药物成分-靶标”;网络。在STRING上进行蛋白-蛋白相互作用(PPI)网络分析。使用R语言进行基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析。采用分子对接对核心靶点进行验证。采用左冠状动脉前降支结扎法建立小鼠心肌梗死致心力衰竭模型。将造模小鼠分为假手术组、模型组、低、中、高剂量组(分别为2.34、4.68、9.36 g·kg~(-1))和卡托普利组(3.25 mg·kg~(-1))。连续给药6周后,采用多普勒超声成像系统检测心功能指标:左室射血分数(LVEF)、左室缩短分数(LVFS)、左室收缩末尺寸(LVIDs)、左室舒张末尺寸(LVIDd)。用苏木精-伊红染色观察心肌组织形态学变化。RT-qPCR检测心肌组织中微管相关蛋白1轻链3 β (LC3B)、Beclin1、p62、HIF-1α、HO-1 mRNA表达水平。Western blot检测LC3B、beclin1、p62、自噬相关蛋白5(ATG5)、HIF-1α、HO-1蛋白水平。结果表明,获得了LGZGD的103个有效成分,对应224个靶标。共检索到心肌梗死相关靶点3 485个,CHF相关靶点6 165个。GSE16499数据集获得了3 263个差异表达基因。共有31个共同目标。前3位的核心活性成分为槲皮素、柚皮素和1-甲氧基phaseolidin。拓扑分析结果显示,核心靶点为MAPK3、HMOX1(HO-1)、MYC、ADRB2、PPARD和HIF1A(HIF-1α)。分子对接结果表明,核心靶点与LGZGD的主要活性成分结合较强。LGZGD能明显改善小鼠心功能,减轻心肌组织病理改变。Western blot和RT-qPCR结果显示,模型组大鼠HIF-1α/HO-1信号通路激活,细胞自噬活性增强。LGZGD上调LC3B、Beclin1、ATG5、HIF-1α和HO-1水平,下调p62 mRNA和蛋白水平。综上所述,LGZGD可通过上调HIF-1α/HO-1信号通路,增强心肌梗死后小鼠CHF模型的自噬,改善心功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Zhongguo Zhongyao Zazhi
Zhongguo Zhongyao Zazhi Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)
CiteScore
1.50
自引率
0.00%
发文量
581
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