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Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways.

ABSTRACT: Background: Chronic heart failure (CHF) is a major public health problem with high mortality and morbidity worldwide. Shexiang Tongxin Dropping Pill (STDP) is a widely used traditional Chinese medicine preparation for coronary heart disease and growing evidence proves that STDP exerts beneficial effects on CHF in the clinic. However, the molecular mechanism of the therapeutic effects of STDP on CHF remains largely unknown. Objective: This study aimed to elucidate the mechanism of action of STDP against CHF by integrating network pharmacology analysis and whole-transcriptome sequencing. Methods: First, the mouse model of CHF was established by the transverse aortic constriction (TAC) surgery, and the efficacy of STDP against CHF was evaluated by assessing the alterations in cardiac function, myocardial fibrosis, and cardiomyocyte hypertrophy with echocardiography, Masson's trichrome staining, and wheat germ agglutinin staining. Next, a CHF disease network was constructed by integrating cardiovascular disease-related genes and the transcriptome sequencing data, which was used to explore the underlying mechanism of action of STDP. Then, the key targets involved in the effects of STDP on CHF were determined by network analysis algorithms, and pathway enrichment analysis was performed to these key genes. Finally, important targets in critical pathway were verified in vivo. Results: STDP administration obviously improved cardiac function, relieved cardiomyocyte hypertrophy, and ameliorated myocardial fibrosis in CHF mice. Moreover, STDP significantly reversed the imbalanced genes that belong to the disease network of CHF in mice with TAC, and the number of genes with the reverse effect was 395. Pathway analysis of the crucial genes with recovery efficiency revealed that pathways related to fibrosis and energy metabolism were highly enriched, while TGF-β pathway and ERK/MAPK pathway were predicted to be significantly affected. Consistently, validation experiments confirmed that inhibiting ERK/MAPK and TGF-β signaling pathways via reduction of the phosphorylation level of Smad3 and ERK1/2 is the important mechanism of STDP against CHF. Conclusion: Our data demonstrated that STDP can recover the imbalanced CHF network disturbed by the modeling of TAC through the multi-target and multi-pathway manner in mice, and the mechanisms are mainly related to inhibition of ERK/MAPK and TGF-β signaling pathways.

SUBMITTER: Zhang S

PROVIDER: S-EPMC8682969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Chronic heart failure (CHF) is a major public health problem with high mortality and morbidity worldwide. Shexiang Tongxin Dropping Pill (STDP) is a widely used traditional Chinese medicine preparation for coronary heart disease and growing evidence proves that STDP exerts beneficial effects on CHF in the clinic. However, the mechanism of its effect on CHF still yet to be deciphered. Objective: This study aimed to elucidate the potential pharmacological mechanism of STDP against CHF by integrating network pharmacology analysis and whole-transcriptome sequencing. Methods: First, the mouse model of CHF was established by the transverse aortic constriction (TAC) surgery, and the efficacy of STDP against CHF was evaluated by assessing the alterations in cardiac function, myocardial fibrosis, and cardiomyocyte hypertrophy with echocardiography, Masson's trichrome staining, and wheat germ agglutinin staining. Next, a CHF disease network was constructed by integrating cardiovascular disease-related genes and the transcriptome sequencing data of mouse heart tissue, which was used to explore the underlying mechanism of action of STDP in CHF. Then, the key targets involved in the effects of STDP on CFH were determined by network analysis algorithms, and pathway enrichment analysis was performed to these key genes. Finally, important targets in the critical pathway were verified in vivo. Results: STDP administration (86 mg/kg/d) obviously improved cardiac function, relieved cardiomyocyte hypertrophy, and ameliorated myocardial fibrosis in CFH mice. Moreover, STDP significantly reversed the imbalanced genes that belong to the disease network of CHF in mice with TAC, and the number of genes with the reverse effect was 395. Pathway analysis of the crucial genes with recovery efficiency revealed that pathways related to fibrosis and energy metabolism were highly enriched, while TGF-β pathway and ERK/MAPK pathway were predicted to be significantly affected. Consistently, validation experiments confirmed that inhibiting ERK/MAPK and TGF-β signaling pathways via reduction of the phosphorylation level of Samd3 and ERK1/2 is the important mechanism of STDP against CHF. Conclusion: Our data provided strong evidence that STDP has great potential for the treatment of CHF and the mechanisms are mainly related to inhibition of ERK/MAPK and TGF-β signaling pathways.

Project description:BackgroundMicrovascular angina (MVA) is a group of clinical manifestations of angina pectoris or angina-like chest pain, positive exercise test, and exclusion of epicardial coronary artery spasm, wherein coronary angiography (CAG) does not present obvious epicardial vascular stenosis. Shexiang Tongxin dropping pill (STDP) has the effect of benefiting the Qi and opening the blood vessels, activating blood circulation, and resolving blood stasis. We explored the mechanism of STDP against MVA by network pharmacology and molecular docking.MethodsTraditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), literature search, SwissTargetPrediction database, and high-throughput experiment- and reference-guided database of traditional Chinese medicine (HERB) were applied to identify the active ingredients and targets of STDP. The MVA targets were searched in the databases of GeneCards, Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), DisGeNET, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). The common targets of STDP and MVA were screened. The software RStudio 4.1.3 was used to analyze the enrichment of these targets using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Protein-protein interaction (PPI) network analysis of the common targets was performed using the Search Tool for the Retrieval of Interacting Genes/Genomes (STRING) database. The cytoHubba plug-in of Cytoscape 3.9.1 software was employed to analyze the PPI network and obtain the core targets. Molecular docking was performed to verify the relationship between the core compounds and proteins with AutoDock Tools 1.5.7 and Pymol 2.4.0.ResultsWe identified 93 effective components of STDP, 310 potential targets, 981 MVA targets, and 138 intersectional targets. The potential anti-MVA mechanism of STDP may involve the advanced glycation end products/receptor for advanced glycation end products (AGE-RAGE) signaling pathway in diabetic complications; lipids and atherosclerosis; fluid shear stress; atherosclerosis; the tumor necrosis factor (TNF), interleukin (IL)-17, hypoxia-inducible factor (HIF)-1, and C-type lectin receptor signaling pathways. Further, STDP mainly acts on its targets IL-6, AKT1, STAT3, JUN, and IL-1β to against MVA.ConclusionsThe STDP may exert its therapeutic effects through processes, such as anti-inflammation, promotion of smooth muscle cell proliferation and differentiation, lipid metabolism, immunomodulation, and regulation of cellular autophagy.

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Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways.

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