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Table of Contents
Year : 2022  |  Volume : 8  |  Issue : 4  |  Page : 530-538

The mechanism of Panax Notoginseng in the treatment of heart failure based on biological analysis

1 Xincun Community Health Service Center, Beijing, China
2 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
3 School of Life Science, Beijing University of Chinese Medicine, Beijing, China
4 Department of Cardiovascular Medicine, Cardiorenal Research Laboratory, Mayo Clinic, Rochester, MN, USA

Date of Submission26-Apr-2021
Date of Acceptance24-May-2021
Date of Web Publication16-Sep-2021

Correspondence Address:
Prof. Chun Li
School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029
Dr. Xu Chen
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.WJTCM_56_21

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Objective: This study aimed to explore the mechanism of Panax notoginseng (PNS) in the treatment of heart failure (HF) based on network pharmacology analysis combined with experimental verification. Materials and Methods: The potential targets and key pathways of effective components of PNS in the treatment of HF were revealed using network pharmacology. The postacute myocardial infarction (MI) HF rat model was established by ligating the left anterior descending branch of the coronary artery. The rats were divided into three groups: model, PNS, and fenofibrate groups. PNS (0.75 g/kg) and fenofibrate (10 mg/kg) were administered for 28 days. The efficacy and target mechanism of PNS in the treatment of HF were verified by cardiac ultrasound, Masson staining, and western blotting (WB) techniques. Results: The results of network pharmacology showed that seven potentially active compounds, such as quercetin, were obtained, involving 105 targets of HF; GO function was enriched to 1240 items; and KEGG enrichment covered 1240 signal pathways. The results of echocardiography showed that EF and FS of HF rats after MI were significantly increased, while Left ventricular internal dimension diastole (LVIDd) and Left ventricular internal dimension systole (LVIDs) were significantly decreased (P < 0.001, P < 0.05). Masson staining showed that PNS could reduce the degree of myocardial fibrosis (MF) in HF. The results of WB showed that PNS could reduce the expression of the p-p38-MAPK, transforming growth factor-beta (TGF-β), and Smad3 in HF rats. Conclusion: PNS inhibited MF and treated HF by regulating p-p38 MAPK-TGF-β pathway, which lays a theoretical foundation for further study of its pharmacological mechanism and key target.

Keywords: Heart failure, MAPK pathway, myocardial fibrosis, network pharmacology, Panax notoginseng

How to cite this article:
Peng L, Ma L, Jiang QQ, Tian X, Shao MY, Li CX, Sun XQ, Ma X, Chen X, Li C. The mechanism of Panax Notoginseng in the treatment of heart failure based on biological analysis. World J Tradit Chin Med 2022;8:530-8

How to cite this URL:
Peng L, Ma L, Jiang QQ, Tian X, Shao MY, Li CX, Sun XQ, Ma X, Chen X, Li C. The mechanism of Panax Notoginseng in the treatment of heart failure based on biological analysis. World J Tradit Chin Med [serial online] 2022 [cited 2023 Dec 8];8:530-8. Available from: https://www.wjtcm.net/text.asp?2022/8/4/530/326075

  Introduction Top

Myocardial fibrosis (MF) refers to myocardial calcification caused by continuous and severe myocardial ischemia and hypoxia after myocardial infarction (MI), which is one of the main processes leading to heart failure (HF). The pathogenesis of HF is complicated, and clinical treatment strategies mainly include neuroendocrine inhibition, β-receptor blockers, and diuretics, but the long-term efficacy is not satisfactory. The changes in the interstitial extracellular matrix and coronary microcirculation play an important role in the occurrence and development of pathological myocardial remodeling. The process of myocardial remodeling involves fibrosis in the left ventricular wall, and pathological myocardial remodeling determines the development process of HF. MF is characterized by a diffuse and disproportionate accumulation of myocardial interstitial collagen. MF leads to left ventricular dysfunction in many diseases and makes patients prone to HF with preserved or reduced ejection fraction. Previous studies have confirmed that improving MF can delay the occurrence and development of HF and become an effective intervention for the treatment of HF.[1]

Transforming growth factor-beta 1 (TGF-β1) is a member of the TGF-β superfamily involved in various biological processes, including regulation of cell growth and differentiation and promotion of collagen expression, which is closely related to MF.[2] The TGF-β signal is transmitted to the nucleus through the downstream Smads family, which subsequently leads to imbalance of the type I/III collagen ratio, and finally aggravates the occurrence of MF.[3] MAPK signaling pathway can extensively regulate cell apoptosis and inflammatory response. p38-MAPK belongs to the MAPK family, which is closely associated with cell apoptosis induced by pathological conditions of ischemia and hypoxia after HF. Previous studies have reported that regulating the Ang II Type 1 receptor/p38-MAPK pathway can effectively improve the degree of fibrosis in the ischemic area of rats, thereby alleviating the occurrence and development of HF.[4]

The clinical application of traditional Chinese medicine has proven effective and has made great contributions to the health of Chinese residents for thousands of years. It plays a multicomponent, multitarget, and multichannel regulatory role in cardiovascular diseases, such as MF. The mechanism of traditional Chinese medicine in improving MF in HF remains controversial in the field of traditional Chinese medicine. The traditional Chinese medicine Panax notoginseng (PNS) is widely used in the treatment of clinical cardiovascular diseases with significant curative effect and good safety. Its main effects are promoting blood circulation, removing blood stasis, reducing swelling, and relieving pain.

There are many reports on the pharmacological effects of PNS. PNS can regulate the signal pathways related to inflammation, lipid metabolism, coagulation system, apoptosis, angiogenesis, atherosclerosis, and myocardial ischemia.[5],[6],[7],[8] However, there are few studies on the effect of PNS on HF, especially on the prevention and treatment of MF, and its specific effect mechanism is unclear,[9] which needs to be further elaborated. Network pharmacology is a new discipline that studies the complex biological relationships between drugs and diseases. With its visualization and systematic advantages, it can analyze drug action on different target networks from the levels of protein molecules, regulatory genes, and metabolites; this enables multicomponent and multipoint research that is required for traditional Chinese medicine.[10] In this study, the network of “compound-target-signal pathway-pharmacological action” was constructed to reveal the multitarget and multipathway synergistic mechanism of PNS on MF, and the pathway was verified based on the whole animal experiment. This study provided a new strategy for the treatment of HF.

  Materials and Methods Top

Collection and screening of Panax notoginseng

Based on the TCMSP database (http://tcmspw.com/tcmsp.php) to obtain the ingredient information of PNS (OB ≥30%, DL value ≥0.18).[11] The corresponding targets were preserved for target correction through the Uniprot ID (https://www.uniprot.org/).

There are five inflammatory and fibrosis related pathways mainly involved the tumor necrosis factor (TNF) signaling pathway, the nuclear factor kappa B signaling pathway, hypoxia-inducible factor 1 (HIF-1) signaling pathway, HIF-1 signaling pathway, MAPK signaling pathway and TGF-beta signaling pathway.

Heart failure target and target collection

Using “Heart Failure” as the search keyword, the HF target was searched in the GeneCards (https://www.genecards.org/) and DisGeNET (https://www.disgenet.org/home/) databases;[12] the duplicate genes were deleted using the Excel table and were standardized. Finally, the duplicated items were summarized and eliminated to obtain the target data, and a disease–gene data table was constructed.

Acquisition of core targets of Panax notoginseng in the treatment of heart failure

The screened targets of PNS and HF were superimposed and displayed in a Venn diagram. The obtained targets of the intersection of PNS and HF were imported into the STRING (ELIXIR, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK) (Version 11.0) database to obtain the relationship between potential targets: Select “Multiple proteins” → upload targets → “Organism (species)” selection “Rattus norvegicus (rat)” → check gene information → get protein–protein interaction (PPI) network → download “TSV” format file. The obtained target interaction information was imported into the Image-Pro software (Bio-Rad, Hercules, CA, USA) to construct the PPI network.

GO biological function annotation and KEGG pathway enrichment analysis

The potential targets of PNS in the treatment of HF based on database screening were imported into the DAVID database (https://david.ncifcrf.gov), and the GO and KEGG signal pathway enrichment analyses were performed. The Omicshare online bioinformatics platform (https://www.omicshare.com/quote.php) was used to realize network visualization.

Construction of the visual network of heart failure-drug-active ingredient-targets/pathways

Cytoscape-3.6.2 was used to construct a network of “active ingredients of PNS-key targets for the treatment of HF-key pathways.” The network consists of three parts, namely the active components screened by PNS, the corresponding intersection target proteins with HF, and the potential protein enrichment pathway. The main mechanism of PNS in the treatment of HF was predicted by degree central analysis.


Sprague–Dawley rats with a body weight of 220–240 g were obtained from the Beijing Vital River Laboratory Animal Technology Co., Ltd., China, and housed in a specific pathogen-free animal room of the Beijing University of Chinese Medicine (BUCM). All animal procedures were approved by the Animal Care Committee of BUCM and confirmed by the European Parliament Directive 2010/63/EU on animal protection for the purposes of science. This animal research program has been approved by the Experimental Animal Ethics Committee of BUCM, serial number: BUCM-4-2018001201-1014.

Preparation of a heart failure rat model after myocardial infarction

The postacute MI HF model of rats was prepared by referring to the modeling method established by the previous research group.[13] The specific operation was as follows: The rats weighing 200 ± 10 g were anesthetized by intraperitoneal injection of 1% pentobarbital sodium, according to their body weight, with the dose of 50 mg/kg; they were fixed on the rat plate for skin preparation, and endotracheal intubation was performed with 22G indwelling needle. A chest opener to open the chest cavity between the third and fourth ribs was used to expose the heart, and the left anterior descending coronary artery was ligated with a 5-0 surgical suture. Lidocaine drip was administered after operation to avoid arrhythmia in rats. The rats were sutured with 2-0 surgical sutures, and breathing was observed. After the rats were stable, the ventilator was removed, and they were transferred to an electric blanket; postoperative care was performed until they woke up. Rats in the sham group only underwent thoracotomy procedure without LAD ligation, and the other procedures were the same with the sham group. The rats were randomly divided into model, PNS, and fenofibrate groups 24 h after the operation, with five rats in each group. The PNS (0.75 g/kg) and fenofibrate groups (10 mg/kg) were given the corresponding drugs for 28 days, and the rats in the sham and model groups were given with the same volume of water.

Echocardiographic assessment of cardiac function

After 28 days of intragastric administration, rats in each group were anesthetized by intraperitoneal injection of 1% sodium pentobarbital, and their limbs were fixed on the ultrasound imaging platform of small animals to evaluate the cardiac function. LVIDd and LVIDs parameters were measured, and FS and EF were calculated.

Masson staining

Myocardial tissue was soaked in 50 mL 4% paraformaldehyde. Pathological section preparation included dehydrated paraffin embedding and was cut into 5 μm thick sections for Masson staining. Masson's trichrome staining was performed to assess MF. Image-Pro software (Bio-Rad, Hercules, CA, USA) was used to analyze the image results, calculate the CVF value, and quantitatively evaluate the collagen fiber area.

Western blotting

A 30–40 mg of rat heart tissue was cut; the corresponding volume of RIPA lysis solution (100 mg/mL) was added into a 2 mL crushing tube, balanced, and put into the tissue crushing instrument for homogenization. The 2 mL crushing tube was then removed and centrifuged (parameter setting: 4°C, 12,000 × g, 10 min), and the supernatant was taken to obtain the total protein. The BCA method was used for protein quantification to determine the protein concentration of each group. After the protein loading volume was confirmed, 5 × loading buffer was added (protein volume: 5 × loading buffer = 5:1), and the protein was denatured in a water bath at 95°C. The samples were separated by 10% SDS-PAGE gel electrophoresis and transferred to a PVDF membrane by wet transfer. A 5% skimmed milk powder was sealed, and the corresponding primary antibodies (p-p38 MAPK, TGF-β1, Smad3, and GAPDH) were incubated, respectively, and placed in a refrigerator at 4°C overnight. The supernatant was removed and washed with PBS three times for 10 min each. After incubating the secondary antibody for 1 h, it was washed with PBS three times for 10 each. Finally, the luminescent liquid was dropped on the PVDF film, and a gel imager for exposure by UVP BioImaging Systems (Bio-Rad, Hercules, CA, United States) and Image Lab software for grayscale analysis were used.

Statistical analysis

Data were presented as mean ± standard deviation. Differences among groups were analyzed by one-way analysis of variance (SPSS 20.0 (IBM SPSS STATISTICS 20.0, USA) statistical software or GraphPad Prism 6). Statistical significance was set at P < 0.05. All statistical analyses were carried out using the Prism software.

  Results Top

Main active ingredients of Panax notoginseng

According to OB ≥30% and DL ≥0.18, seven active ingredients from PNS were screened out, and the main ingredients included quercetin, β-sterol, and ginsenoside Rh2. [Table 1] shows the basic information of the specific ingredients. Seven active constituents corresponded to 240 targets, including 151 targets for quercetin, 36 targets for β-sterol, 29 targets for stigmasterol, and 5 targets for ginsenoside Rh2. The results are shown in [Figure 1].
Table 1: Main active ingredients in Panax notoginseng

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Figure 1: Potential target map of the active ingredients of Panax notoginseng

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Prediction of core treatment targets for heart failure

A total of 2427 HF-related targets were obtained from DisgeNet and GeneCards databases (duplicates in both databases were deleted). By intersecting the 182 targets of the seven components of PNS with the 2427 targets, a total of 105 common targets were obtained as potential targets for the treatment of HF by PNS. Through the String database, 105 PPI relationships were obtained. The Cytoscape 3.6.2 software was used to construct a PPI network, and the visualization results were analyzed using the network topology analysis method. The sizes of the nodes in the graph are arranged according to the degree value; the larger the degree value, the larger the node. According to the degree value, the top targets are AKT1, Casp3, MAPK1, CCL2, IL6, Mmp9, IL10, VEGFA, Tp53, and TGF-β. The result is shown in [Figure 2].
Figure 2: Potential core targets of Panax notoginseng in the treatment of heart failure

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GO function and KEGG pathway enrichment analyses of heart failure

GO analysis was performed on 105 potential targets, including the biological process, cell component, and molecular function of target genes. A total of 1240 items of information were obtained. Biological processes mainly involved the response to hypoxia, lipopolysaccharide, and the active regulation of apoptosis. Molecular functions mainly involved protein binding and transcription factor binding. The first 20 items were selected to draw a histogram [Figure 3]. KEGG pathway enrichment analysis results showed that a total of 150 enrichment results were obtained (P < 0.01). The first 20 relevant signal pathways were selected and visualized through bubble graphs [Figure 4]. There are five inflammatory and fibrosis related pathways mainly involved the tumor necrosis factor (TNF) signaling pathway, the nuclear factor kappa B signaling pathway, hypoxia-inducible factor 1 (HIF-1) signaling pathway, HIF-1 signaling pathway, MAPK signaling pathway and TGF-beta signaling pathway.
Figure 3: GO biological annotation of Panax notoginseng in the treatment of heart failure

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Figure 4: KEGG pathway enrichment analysis of Panax notoginseng in the treatment of heart failure

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Construction of the visual network of heart failure-drug-active ingredient-targets/pathways

The Cytoscape-3.6.2 was used to construct the diagram of “active ingredients of PNS-key target for the treatment of the HF-key pathway” [Figure 5]. As shown in [Figure 5], the blue triangle represents PNS, the yellow circle represents the target point, and the pink square represents the path of action. From the network diagram and node information, it showed that seven active ingredients are closely related to 18 key signal pathways. The main action pathways are the inflammatory fibrosis- and apoptosis-related pathways, including TNF signaling pathway, MAPK signaling pathway, TGF-beta signaling pathway, and apoptosis pathway, and the main components are quercetin and β-sterol. This study preliminarily revealed the mechanism of the multicomponents of PNS acting on multitargets and multipathways.
Figure 5: “Panax notoginseng-key target, key pathway-heart failure” network

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Effects of Panax notoginseng on cardiac function in heart failure rats

Echocardiography showed that compared with the sham group, [Figure 6]. LVIDs and LVIDd of the model group increased by 185% and 146%, respectively (P < 0.001, P < 0.001), while EF and FS decreased by 48% and 59%, respectively (P < 0.001, P < 0.001), suggesting that the HF rat model was successfully established. Compared with the model group, LVIDs and LVIDd of the PNS group were reduced by 12% and 22%, respectively (P < 0.05, P < 0.01), while EF and FS were increased by 32% and 59%, respectively (P < 0.05, P < 0.05), indicating that PNS can significantly increase the EF of HF rats, thereby improving cardiac function. In addition, fenofibrate had similar effects as PNS.
Figure 6: Ultrasound image of the rat (compared with model group, *P < 0.05, **P < 0. 01, ***P < 0.001)

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Effect of Panax notoginseng on pathological morphology of myocardial tissue in heart failure rats

As indicated by Masson staining results in [Figure 7], cardiomyocytes of rats in the sham group were neatly arranged without collagen fiber distribution, whereas cardiomyocytes in the model group were diffusely arranged and showed the degree of MF increased significantly. Compared with the model group, PNS and fenofibrate can effectively reduce the content of collagen fiber, suggesting that the treatment of PNS can significantly reduce the degree of MF and alleviate the occurrence and development of HF. In addition, the degree of MF was quantified by calculating the collagen volume fraction (CVF). The calculation formula was CVF = collagen fiber area/myocardial surface area × 100%. The results indicated that PNS and fenofibrate reduced collagen deposition by 51.45% and 48.56%, respectively (P < 0.001 P < 0.001), as shown in [Figure 7].
Figure 7: Masson staining results of myocardial histopathology in each group of rats (Compared with the model group, ***P < 0.001)

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Effect of Panax notoginseng on the expression of p-p38-MAPK-transforming growth factor-beta pathway-related proteins

Western blotting results showed that the expression of p-p38-MAPK, TGF-β1, and Smad3 in the model group was significantly increased compared with the sham group (P < 0.001, P < 0.001, P < 0.001), indicating that p-p38-MAPK, TGF-β1, and Smad3 proteins were activated in the heart of rats after HF to play a role in signal transduction and aggravate the occurrence of MF. After 28 days of treatment with PNS, the expressions of p-p38-MAPK, TGF-β1, and Smad3 in the myocardial tissue were all downregulated to varying degrees (P < 0.001, P < 0.001, P < 0.001). The total p38-MAPK protein did not change significantly in the sham group, model group, and drug group (P > 0.05). Fenofibrate also showed the same regulatory results. The study preliminarily revealed that PNS can improve the degree of MF in HF rats by inhibiting the p-p38-MAPK/TGF-β pathway [Figure 8].
Figure 8: Comparison of protein expressions of p-p38 MAPK, Transforming growth factor-beta 1 and Smad3 in myocardial tissue of rats in each group. (Compared with the model group, ***P < 0.001)

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  Discussion Top

HF is the end stage of cardiovascular disease, its high incidence and high mortality are the main problems in clinical treatment, and it increases yearly with the aging population.[14] MI is a major cause of HF.[15] Ischemic cell death during MI leads to multistage repair response; it can also lead to structural changes in the undamaged ventricular wall, triggering reactive remodeling processes including interstitial and perivascular fibrosis. Although initial reparative fibrosis is essential to prevent ventricular wall rupture, excessive fibrosis and reactive fibrosis outside the injured area can lead to the damage of cardiac function and eventually to HF. Therefore, abrogation of cardiac fibroblast transformation into myofibroblasts is a strategy to suppress cardiac fibrotic remodeling, which can lead to HF. MF is the main pathological change of MI area in patients with MI. It is usually accompanied by a large degree of proliferation and migration, which promotes the loss of original structure and function of fibroblasts, and causes abnormal ventricular diastolic dysfunction.[16],[17] Reducing the degree of MF after MI is a new strategy for the treatment of HF, which mainly includes inhibiting the development of fibrosis in the noninfarct area of the myocardium, preventing further aggravation of fibrosis, and thus improving cardiac function.

In this study, seven active ingredients including quercetin, β-sitosterol, and ginsenoside Rh2 were screened out through network pharmacology. Quercetin has an adjunctive therapeutic effect on patients with coronary heart disease, and its pharmacological effects include lowering blood pressure, lowering blood lipids, and dilating coronary arteries;[18] β-sterol has certain anti-inflammatory, anti-oxidation, anti-atherosclerosis, and lipid-lowering effects and plays an important role in the regulation of liver metabolism, cardiovascular disease, and diabetes mellitus.[19] Ginsenoside Rh2 alleviates myocardial injury in rats with myocardial ischemia/reperfusion by increasing serum VEGF level.[20] By comparing and analyzing seven potential active ingredient action targets and HF-related targets, it is found that there are 105 overlapping target genes between the potential active ingredients of PNS and HF. These 105 target genes may be the target of PNS in the treatment of HF. The interaction network for the treatment of HF of notoginseng was constructed based on String database. Core targets, such as AKT1, CASP3, MAPK1, CCl2, IL6, MMP9, IL10, VEGFA, TP53, and TGF-β, were screened out according to the median of degree ≥2 of PPI network topological parameter node. Akt can mediate PI3K-dependent pathways in vivo and regulate cell apoptosis, which mainly plays a role by activating Casp3, a member of the caspase family.[21] MAPK has significant effects on the regulation of inflammatory response and apoptosis.[22] Interleukin (IL) 10 is an anti-inflammatory factor that inhibits the release of inflammatory cytokines TNF and IL-6 through the activation of macrophages.[23] TGF-β is a key target of the network and may play an important role in the treatment of HF by PNS. As an important contributing factor of MF, TGF-β can activate fibroblasts, stimulate the synthesis of collagen fibers, and accelerate the deposition of extracellular matrix.[24] The results of GO enrichment analysis showed that the molecular functions of PNS in the treatment of HF involve many biological processes such as cytokine regulation, cell proliferation and apoptosis, and hypoxia.

To explore the potential mechanism of PNS in the treatment of HF and find out whether the potential anti-MF pathway is related to TGF-β, the KEGG pathway was analyzed in this study. Among the top 20 related pathways of PNS in the treatment of HF include TNF signaling pathway, MAPK signaling pathway, TGF-β signaling pathway, and apoptosis pathway. Among them, p-p38-MAPK/TGF-β signaling pathway is closely related to MF, which is widely involved in the transduction of a variety of signals. This study preliminarily predicted that the p38-MAPK/TGF-β signaling pathway would be activated in cardiomyocytes after the occurrence of HF, thus exacerbating the degree of MF. The network pharmacological results of this study suggest that PNS may reduce the degree of MF after MI by inhibiting the activation of the p38-MAPK/TGF-β signaling pathway. Therefore, animal experiments were carried out to verify the p38-MAPK/TGF-β pathway.

In this study, left anterior descending ligation was performed to induce a HF rat model; the effects of PNS on cardiac function and MF in rats with HF were evaluated from the perspective of cardiac function and histopathology. Echocardiographic indicated that LVIDs and LVIDd in the model group were increased by 185% and 146% (P < 0.01), respectively, and EF and FS were decreased by 48% and 59% (P < 0.01), respectively, proving that the model was successful. PNS administration group LVIDs and LVIDd significantly decreased compared with model group, and EF and FS were also significantly increased, indicating that after the intervention of PNS, the cardiac function of HF rats could be improved by enhancing the ejection fraction. MF is the most important mechanism of cardiac remodeling after MI,[25],[26] and inhibition of MF is conducive to the reversal of ventricular remodeling after MI.[27] Further, Masson staining results showed that the collagen in HF rats was significantly increased, and MF lesions occurred in the MI area. Compared with the model group, the collagen hyperplasia in the PNS group was significantly reduced, indicating that PNS reduced the collagen hyperplasia in HF rats and inhibited the degree of MF. In this study, PNS improved the MF level of HF rats by inhibiting the expression of p38-MAPK/TGF-β pathway-related proteins.

  Conclusion Top

In summary, this study predicted the potential pathways of PNS in the treatment of HF through network pharmacology used the HF rat model for experimental verification and found the mechanism of regulating the p-p38-MAPK/TGF-β pathway to inhibit MF and prevent HF. This study provides an experimental basis for the clinical improvement of the occurrence and development of HF and also offers a new treatment strategy for the prevention and treatment of HF.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (grant number 81822049) and the Major New Drug Creation of the Ministry of Science and Technology (grant number 2019ZX09201004-001-011).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

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