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

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 eff...

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Autores principales:	Shuying Zhang, Hanbing Liu, Qianqian Fang, Houhong He, Xiaoyan Lu, Yi Wang, Xiaohui Fan
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Shexiang Tongxin dripping pill chronic heart failure network pharmacology whole-transcriptome sequencing ERK/MAPK signaling pathway TGF-β signaling pathway Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3ea1dc6e6b684d92b26f1043dc3b13ea
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spelling	oai:doaj.org-article:3ea1dc6e6b684d92b26f1043dc3b13ea2021-12-03T06:58:17ZShexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways1663-981210.3389/fphar.2021.796354https://doaj.org/article/3ea1dc6e6b684d92b26f1043dc3b13ea2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.796354/fullhttps://doaj.org/toc/1663-9812Background: 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.Shuying ZhangHanbing LiuQianqian FangHouhong HeXiaoyan LuXiaoyan LuYi WangXiaohui FanXiaohui FanXiaohui FanFrontiers Media S.A.articleShexiang Tongxin dripping pillchronic heart failurenetwork pharmacologywhole-transcriptome sequencingERK/MAPK signaling pathwayTGF-β signaling pathwayTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Shexiang Tongxin dripping pill chronic heart failure network pharmacology whole-transcriptome sequencing ERK/MAPK signaling pathway TGF-β signaling pathway Therapeutics. Pharmacology RM1-950
spellingShingle	Shexiang Tongxin dripping pill chronic heart failure network pharmacology whole-transcriptome sequencing ERK/MAPK signaling pathway TGF-β signaling pathway Therapeutics. Pharmacology RM1-950 Shuying Zhang Hanbing Liu Qianqian Fang Houhong He Xiaoyan Lu Xiaoyan Lu Yi Wang Xiaohui Fan Xiaohui Fan Xiaohui Fan Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways
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 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.
format	article
author	Shuying Zhang Hanbing Liu Qianqian Fang Houhong He Xiaoyan Lu Xiaoyan Lu Yi Wang Xiaohui Fan Xiaohui Fan Xiaohui Fan
author_facet	Shuying Zhang Hanbing Liu Qianqian Fang Houhong He Xiaoyan Lu Xiaoyan Lu Yi Wang Xiaohui Fan Xiaohui Fan Xiaohui Fan
author_sort	Shuying Zhang
title	Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways
title_short	Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways
title_full	Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways
title_fullStr	Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways
title_full_unstemmed	Shexiang Tongxin Dropping Pill Protects Against Chronic Heart Failure in Mice via Inhibiting the ERK/MAPK and TGF-β Signaling Pathways
title_sort	shexiang tongxin dropping pill protects against chronic heart failure in mice via inhibiting the erk/mapk and tgf-β signaling pathways
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3ea1dc6e6b684d92b26f1043dc3b13ea
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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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