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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 5  |  Issue : 4  |  Page : 220-227

Study on the mechanism of qingre huoxue prescription in the intervention and treatment of acute myocardial infarction based on network pharmacology


1 Pharmacology Major of Integrated Traditional Chinese and Western Medicine, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing, China
2 Harvard Medical School, 25 Shattuck Street Boston, MA 02115, USA
3 Scientific Research and Experiment Center, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China

Date of Submission09-Nov-2018
Date of Decision29-Mar-2019
Date of Acceptance08-Apr-2019
Date of Web Publication03-Dec-2019

Correspondence Address:
Dr. Jian-Xin Chen
Pharmacology Major of Integrated Traditional Chinese and Western Medicine, School of Preclinical Medicine, Beijing University of Chinese Medicine, Beijing
China
Dr. Kuo Gao
Scientific Research and Experiment Center, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_15_19

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  Abstract 


Objective: The objective is to study the mechanism of Qingre Huoxue prescription in the intervention and treatment of acute myocardial infarction (AMI) based on the method of network pharmacology. Materials and Methods: Five databases were used to screen the chemical compounds and targets of Ligusticum wallichii (chuanxiong), Radix Paeoniae Rubra (chishao), Lignum acronychiae (jiangxiang), Safflower (honghua), Salvia miltiorrhiza (danshen), Scutellaria baicalensis (huangqin), and Ilex pubescens (mao dong qing) in Qingre Huoxue prescription. Furthermore, Cytoscape-V3.2.1 software was used to construct the drug-component-target network. Functional protein association networks' database and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used to visualize the protein interaction, pathway enrichment, and analysis. Results: A total of 44 active ingredients were screened out in Qingre Huoxue prescription. Among them, 178 targets and 41 compounds related to Qingre Huoxue prescription's function in treating AMI were obtained. After the analysis of the drug-component-action target network on Qingre Huoxue prescription, 14 key compounds and nine key targets with three scores above average were obtained. In addition, pathway enrichment and biological processes were conducted with the aid of the DAVID; and 8 related pathways and 10 biological processes were associated with AMI and related diseases; the PI3K-AKT signaling pathway, MAPK signaling pathway, and HIF-1 signaling pathway are the main pathways of Qingre Huoxue prescription for the treatment of AMI and related diseases. Conclusion: Qingre Huoxue prescription could treat AMI by multiple components, targets, and pathways. This study provides ideas and theoretical basis for further clinical studies on Qingre Huoxue prescription in treating AMI.

Keywords: Acute myocardial infarction, mechanism, network pharmacology, Qingre Huoxue prescription


How to cite this article:
Jia CX, Wang JP, Zhang FL, Pang XH, Wang WL, Xu PX, Gao K, Chen JX. Study on the mechanism of qingre huoxue prescription in the intervention and treatment of acute myocardial infarction based on network pharmacology. World J Tradit Chin Med 2019;5:220-7

How to cite this URL:
Jia CX, Wang JP, Zhang FL, Pang XH, Wang WL, Xu PX, Gao K, Chen JX. Study on the mechanism of qingre huoxue prescription in the intervention and treatment of acute myocardial infarction based on network pharmacology. World J Tradit Chin Med [serial online] 2019 [cited 2019 Dec 8];5:220-7. Available from: http://www.wjtcm.net/text.asp?2019/5/4/220/271984




  Introduction Top


In recent years, the incidence of cardiovascular disease in China was increasing year by year. The number of patients with coronary heart disease is over 1 million every year in China, which seriously affects the normal living standards of people. Acute myocardial infarction (AMI) is a common cardiovascular disease. It could cause harm in a short period and lead to death in severe cases.[1] AMI is an acute myocardial necrosis caused by myocardial ischemia and hypoxia induced by coronary artery disease. Some studies have shown that AMI is closely related to plaque inflammation. Animal experiments have proved that the use of traditional Chinese medicine (TCM) with effect of clearing heat and activating blood circulation could suppress the occurrence and development of plaque.[2],[3],[4]

Qingre Huoxue prescription is composed of Ligusticum wallichii (chuanxiong, 10 g); Radix Paeoniae Rubra (chishao, 12 g); Lignum acronychiae (jiangxiang, 10 g); Safflower (honghua, 10 g); Salvia miltiorrhiza (danshen, 30 g); S. baicalensis (huangqin, 15 g); and Ilex pubescens (mao dong qing, 30 g).[5] Among them, Ligusticum wallichii is warm natured, which could activate blood and circulation of qi, expel wind, and alleviate pain; Radix Paeoniae Rubra is cold-natured, which could clear heat and cool blood as well as dispel stasis and alleviate pain; Lignum acronychiae is warm-natured, which could not only dispel blood stasis and stanch bleeding but also regulate qi to alleviate pain; Safflower is warm-natured, which could activate blood to regulate menstruation and dispel stasis to relieve pain; Salvia miltiorrhiza is slightly cold-natured, which could activate blood and dispel stasis, regulate menstruation and relieve dysmenorrhea, and cool blood and eliminate carbuncle; S. baicalensis is bitter and cold-natured, which could clear heat and dampness, purge fire and resolve toxin, and relieve pain and tranquilize mind;[6] Ilex pubescens is slightly cold-natured, which could activate blood circulation, clear heat and resolve toxin, and disperse swelling and relieve pain.[7] Wu et al.[5] collected 60 patients with AMI and treated them with routine western medicine and add Qingre Huoxue prescription; in addition, it was found that Qingre Huoxue prescription could improve the level of proof factorsin vivo and the score of clinical syndromes compared with routine treatment alone. However, there are many herbs and complex chemical components in this prescription. The mechanism of multi-target and multi-channel treatment for AMI of coronary heart disease still needs further clarification. Network pharmacology integrates multi-disciplinary techniques and methods' it explores the relationship between drugs and diseases from the whole and is consistent with the overall concept of TCM.[8]

This paper adopts the method of network pharmacology to study the mechanism of Qingre Huoxue prescription in treating AMI of coronary heart disease, aiming to provide more information and ideas for the clinical treatment of AMI of coronary heart disease.


  Materials and Methods Top


Selection of objective compounds from Qingre Huoxue prescription

Qingre Huoxue prescription consists of Ligusticum wallichii, Radix Paeoniae Rubra, Lignum acronychiae, Safflower, Salvia miltiorrhiza, S. baicalensis, and Ilex pubescens. TCM Systems Pharmacology Database and Analysis Platform (TCMSP database, http://lsp.nwu.edu.cn/tcmsp.php) and literature were used to collect chemical constituents;, the names of TCMs, such as “chuanxiong,” “chishao,” and “honghua” were input in the TCMSP database. Literature search made use of CNKI and PubMed to search articles on seven TCMs; those Keyword Advertisings were “chuanxiong, chishao, jiangxiang, honghua, danshen, huangqin, mao dong qing,” “Ligusticum wallichii, Radix Paeoniae Rubra, Lignum acronychiae, Safflower, Salvia miltiorrhiza, S. baicalensis, and Ilex pubescens” and then obtained relevant ingredients of TCM according to the contents and inquired whether the obtained ingredients were related to AMI and related diseases. According to other reports, chemical constituents were selected under the conditions of drug-likeness (DL) >0.18 and oral bioavailability (OB) >30%.[9] Compounds that are inconsistent with OB and DL conditions were retained because these compounds have been reported to have important effects on cardiovascular diseases such as AMI. After obtaining seven alternative compounds of TCM, PubChem database was used to further screen the compounds with experimental verification targets for reserve.

The acquisition of Qingre Huoxue prescription targets and related targets of acute myocardial infarction

PubChem database was used to query the target information of compounds screened in the previous step, and active targets were selected. Gene names corresponding to each target protein were obtained in UniProt database (https://www.uniprot.org/). Unless human targets were excluded, UniProt numbers corresponding to the target were recorded. Drugbank database (https://www.drugbank.ca/), Online Mendelian Inheritance in Man database (OMIM, http://www.omim.org/) and GeneCards database (The Human Gene Database, https://www.genecards.org/) were used to search related targets of AMI and to delete duplication. And then, these targets related to acute myocardial infarction were mapped with the targets of Qingre Huoxue Prescription, targets of Qingre Huoxue Prescription in treating AMI were obtained finally.

Network construction and analysis

The obtained targets were processed with Cytoscape-V3.2.1 software, and the network diagram of TCM component target was obtained through the Merge function. In addition, the functional protein association networks' database (String database) was used for the construction of protein mutual network.

Kyoto Encyclopedia of Genes and Genomes pathway enrichment and gene ontology biological process analysis

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and gene ontology (GO) biological analysis were conducted through using The Database for Annotation, Visualization, and Integrated Discovery (DAVID database), to predict the mechanism of Qingre Huoxue prescription in the treatment of AMI.


  Results Top


Selection of objective compounds from Qingre Huoxue prescription

DL refers to the similarity between compound molecules and known drug molecules, which integrates pharmacokinetics and safety and has a great influence on pharmacology research. At the same time, oral availability (OB) is an important parameter for drugs entering the circulatory system through oral administration, and it has important guiding significance for drug research and development.[10] The chemical constituents were screened under the conditions of DL >0.18 and OB >30%. Through the screening of TCMSP, superadd literature, and PubChem, a total of 53 compounds were obtained (The duplication between the herbs is not removed). After removing duplication, 44 compounds were obtained, as shown in [Figure 1]. Among the compounds collected, luteolin, beta sterols, baicalin, and others appeared in a variety of medicinal materials with extensive pharmacological activities.
Figure 1: Objective active compounds of Qingre Huoxue prescription

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The acquisition of Qingre Huoxue prescription targets and related targets of acute myocardial infarction

PubChem database was used to search target information of compounds screened from Qingre Huoxue prescription and to select active targets. For compounds sharing a target, removing duplicates, and retaining only one, then 29 targets related to Ligusticum wallichii, 190 targets related to Radix Paeoniae Rubra, 37 targets related to Lignum acronychiae, 154 targets related to Safflower, 173 targets related to S. miltiorrhiza, 154 targets related to S. baicalensis, and 69 targets related to Ilex pubescens were obtained. Combining the targets of all compounds, 409 targets were obtained after removal of duplication. Drugbank database, OMIM, and Genecards database were used to search acute myocardial infarct-related targets; a total of 2661 targets of AMI were obtained after removing duplicates. By mapping the targets corresponding to Qingre Huoxue prescription, 178 targets and 41 compounds related to Qingre Huoxue prescription in treating AMI were obtained as shown in [Table 1].
Table 1: 178 targets and 41 compounds related to Qingre Huoxue prescription in treating acute myocardial infarction

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Network construction and analysis

CytoscapeV3.2.1(U.S. National Institute of General Medical Sciences (NIGMS)) was used to construct the drug component action-target network of Qingre Huoxue prescription, as shown in [Figure 2]. The green squares represent five herbs, the orange rhomboids represent 41 compounds, and the yellow circles represent 178 targets. Based on the Cytoscape-V3.2.1 network analysis data, compounds and targets were screened according to degrees of freedom, median centrality, and tight centrality, and 14 key compounds and 9 key targets with three scores above average were obtained at last (shows a large scale), and most of these were from S. miltiorrhiza and Safflower as shown in [Table 2] and [Table 3].
Figure 2: Drug-component-target network map

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Table 2: Results of network analysis on key active components of Qingre Huoxue prescription in the treatment of acute myocardial infarction

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Table 3: The key target information and network analysis results of Qingre Huoxue prescription in the treatment of acute myocardial infarction

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The String database could be used to search known interactions between proteins and to predict direct interactions between proteins. We used String database to construct protein interaction network for the treatment of AMI targets about Qingre Huoxue prescription excluding nonhuman targets, as shown in [Figure 2].

The top three of these compounds in terms of degrees of freedom were ellagic acid, luteolin, and chrysin. Ellagic acid has been reported to be able to prevent dietary atherosclerosis in wild-type mice,[11] luteolin could significantly improve cardiac function and reduce the release of myocardial enzymes and inflammatory cytokines after myocardial infarction,[12] and chrysin is a natural flavonoid that could reduce infarct size and alleviate inflammation and oxidative stress in mice after acute ischemic stroke.[13]

Among these nine key targets screened out according to degrees of freedom, median centrality, and tight centrality, androgen receptor (AR) is widely presented in the cardiovascular and cerebrovascular system. Studies have shown that bone marrow mesenchymal stem cells (bm-mscs) could improve the cardiac function of AMI, and bm-mscs also have ARs.[14],[15] Aldose reductase (gene AKR1B1) exists in nerve, heart, and other tissues. Inhibiting aldose reductase can improve the energy supply of ischemic myocardium and can reduce ischemic injury of myocardium.[16] Glycogen synthase kinase-3 (GSK-3) beta belongs to the highly conserved serine/threonine phosphokinase family and it plays a key role in the cardiovascular system. Many myocardial protective drugs are finally focusing on the target of GSK-3 through a variety of signaling pathways, which could increase the phosphorylation of Ser9, reduce mPTP opening to protect the myocardium, and affect the differentiation of stem cells into cardiac myocytes.[17] The treatment of AMI by Qingre Huoxue prescription may be related to the inhibited expression of aldose reductase, increased expression of AR, and overexpression of GSK-3 of the myocardial stem cells about differentiate myocardial cells to repair damaged cardiac tissue, thereby improving cardiac function.

The String database could be used to search for known interactions between proteins and to predict direct interactions between proteins. We used String database to construct protein interaction network for the treatment of AMI targets with Qingre Huoxue prescription excluding nonhuman targets, as shown in [Figure 3]. In the network, nodes with a high degree of values play important roles in the connection of the network, the MAPT gene ranked the first in degree and plays an important role in the MAPK signaling pathway, and MAPK inhibitors could inhibit endoplasmic reticulum stress and could reduce myocardial apoptosis.
Figure 3: Protein interaction network of Qingre Huoxue prescription in the treatment of acute myocardial infarction

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Enrichment of Kyoto Encyclopedia of Genes and Genomes pathway and biological process analysis of gene ontology

KEGG pathway enrichment and GO bioassay were conducted through using DAVID database; a total of 115 pathways were enriched by KEGG pathway. According to P < 0.05 and literature screening, eight KEGG pathways and 10 biological pathways were associated with AMI and related diseases, as shown in [Figure 4]a and [Figure 4]b. The numbers in [Figure 4]a and b represent the number of predicted targets enriched in this pathway. That is to say, the target of TCM ingredients may play a role in the pathways.
Figure 4: (a) Kyoto Encyclopedia of Genes and Genomes pathway diagram of Qingre Huoxue prescription in the treatment of acute myocardial infarction. (b) gene ontology biological process diagram of Qingre Huoxue prescription in the treatment of acute myocardial infarction

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As can be seen from [Figure 4]a and b, the PI3K-AKT signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, and other pathways are the main pathways for the treatment of AMI and related diseases by Qingre Huoxue prescription. Biological processes involve cellular response to hypoxia and positive regulation of angiogenesis, etc., Studies have shown that PI3K-AKT signaling pathway plays a role in promoting angiogenesis and in improving cardiac function after myocardial infarction was activated. Vascular endothelial growth factor (VEGF) is an important regulator of neovascularization. It could effectively promote ischemic myocardial collateral circulation, increase VEGF expression, and promote angiogenesis.[18] In the Qingre Huoxue prescription, 27 targets were involved in PI3K-AKT signaling pathway, which is the highest. It plays a role in promoting angiogenesis after myocardial infarction and in improving cardiac function after activation, and it is an important signaling regulation pathway in platelet activation.[19],[20] Platelet activation pathway plays a regulatory role in the process of Platelet adhesion and aggregation. In the biological process of GO, positive regulation of angiogenesis also indicated that the treatment of AMI with Qingre Huoxue prescription might be related to angiogenesis and platelet activation, which may be achieved through the activation of PI3K-AKT signaling pathway. The mortality of heart failure after AMI is extremely high, which is related to the apoptosis of cardiac myocytes. MAPK inhibitors could inhibit endoplasmic reticulum stress and reduce myocardial apoptosis, suggesting that MAPK signaling pathway plays an important role in AMI myocardial apoptosis. Qingre Huoxue prescription may treat AMI by weakening the apoptosis of AMI cells damaged by MAPK signaling pathway. HIF-1 is a nucleoprotein produced by cells under hypoxia that consists of alpha and beta subunits. It has a protective effect on myocardial cells, and it can promote angiogenesis and glycolysis. Increased expression of HIF-1alpha gene could increase content of VEGF in the blood, increase myocardial capillary density, and reduce myocardial infarction area.[21] The expression of proteins related to the JAK-STAT channel has a protective effect on myocardial ischemia-reperfusion injury, and studies have shown that the myocardial infarction area can be reduced through the mediation of the JAK-STAT cell signaling pathway.[22] In addition, myocardial infarction could cause death and loss of myocardial cells, immune system disorders, and inflammation. Toll-like receptors play a crucial role in inducing immune and inflammatory responses.[23]


  Discussion Top


At present, cardiovascular diseases are still top in the world list of fatal diseases, and the fatality rate caused by AMI is also increasing year by year. For AMI, conventional chemical therapy has certain limitations in clinical treatment.[24] In the field of TCM, AMI belongs to the category of “eclampsia” and “genuine heartache.” It is very promising to use Chinese herbs such as Spina date seed, Dalbergia odorifera, Radix puerariae, and Angelica sinensis as a complementary therapy to the treatment and prevention of cardiac remodeling after AMI.[25] According to relevant studies, Qingre Huoxue prescription could improve the level of inflammatory factors in patients with AMI on the basis of Western medicine treatment, and it is good in terms of safety.[5] Modern pharmacological studies have shown that Safflower has antithrombosis and antiatherosclerosis effects.[26]S. miltiorrhiza has protective effects on myocardium, vasodilation, and antiatherosclerosis.[27] Radix Paeoniae Rubra has antithrombosis, antioxidation, and cardioprotection effects.[28] Ligusticum wallichii has protective effect on myocardium and antiplatelet aggregation;[29]S. baicalensis has anti-inflammatory, antitumor, and antiangiogenesis effects.[30] Lignum acronychiae has vasodilation, antioxidation, anti-inflammatory, and other effects.[31] Ilex pubescens has effects of lowering blood pressure, anticoagulation, and anti-inflammation and improving immunity.[32] However, the mechanism of Qingre Huoxue prescription in treating AMI is not clear.

Based on the method of network pharmacology, this study investigated the relevant targets of Qingre Huoxue prescription in the intervention of AMI and speculated the possible mechanism of Qingre Huoxue prescription in the treatment of AMI. The results showed that the different components in the Qingre Huoxue prescription have similar or common targets and maybe have synergistic effects. Safflower and S. miltiorrhiza are the compounds with the largest number of targets; they might be the important effective Chinese medicine for clearing heat and activating blood circulation. Targets of intervention for AMI include androgen receptor, aldose reductase, and GSK-3 beta. Further, studies on the treatment of AMI with Qingre Huoxue prescription-related pathways involved arachidonic acid metabolism, VEGF signaling pathway, JAK-STAT signaling pathway, Toll-like receptor signaling pathway, platelet activation, HIF-1 signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway.

This study revealed the molecular basis and mechanism of Qingre Huoxue prescription in the intervention of AMI, laying a foundation for the development of TCM. However, there are also some limitations, such as imperfect database information may lead to omission of compounds and targets; because of the author's cognitive deficiencies, the interpretation might not be comprehensive; lack of experimental verification to prove the accuracy of prediction. Therefore, it is imperative to further study compounds and targets in the future from the experimental perspective on the intervention of Qingre Huoxue prescription in the treatment of AMI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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