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Published on: June 3, 2018
Xijiaqi Formula attenuates myocardial infarction-induced chronic heart failure by inhibiting TGF-β1/Smads-mediated
Qian Zhang1, Jie Chen1, Lin-Nan Zhou2
1Key Laboratory of Chinese Internal Medicine of Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
Insights
Xijiaqi Formula (XJQ) improves heart function after myocardial infarction by inhibiting fibroblast activation and regulating extracellular matrix remodeling. This study clarifies the mechanism of XJQ in treating chronic heart failure (CHF).
Area of Science:
- Cardiovascular Research
- Integrative Medicine
- Pharmacology
Background:
- Chronic heart failure (CHF) is a significant complication following myocardial infarction (MI).
- Xijiaqi Formula (XJQ) demonstrates clinical efficacy in treating CHF, but its underlying mechanisms require elucidation.
- Understanding XJQ's mechanism is crucial for optimizing CHF treatment strategies.
Purpose of the Study:
- To investigate the therapeutic effects of XJQ on post-myocardial infarction (MI) chronic heart failure (CHF) in a rat model.
- To elucidate the molecular mechanisms by which XJQ exerts its beneficial effects on cardiac function and structure.
- To identify key molecular targets and pathways modulated by XJQ in the context of CHF.
Main Methods:
- XJQ composition was analyzed using UHPLC-Q-TOF-MS/MS.
- Post-MI CHF was induced in rats via coronary artery ligation; cardiac function was assessed using echocardiography and hemodynamic measurements.
- Myocardial histology, fibrosis, ultrastructure, and transcriptomics were evaluated, alongside in vitro TGF-β1-induced myofibroblast activation assays.
Main Results:
- XJQ treatment significantly improved cardiac function and structure, reducing fibrosis, edema, and mitochondrial damage in MI rats.
- Transcriptomic analysis revealed that XJQ primarily influences genes involved in extracellular matrix (ECM) remodeling.
- XJQ suppressed the upregulation of ECM proteins (e.g., Adamts2, Fbln1, Itgbl1, Ltbp3) and inhibited TGF-β1/Smads signaling and myofibroblast activation in vitro.
Conclusions:
- XJQ effectively attenuates the progression of MI to CHF by inhibiting TGF-β1-mediated fibroblast activation via the Smads signaling pathway.
- The therapeutic effects of XJQ are linked to its regulation of ECM remodeling proteins, including Adamts2, Itgbl1, Fbln1, and Ltbp3.
- This study provides mechanistic insights into XJQ's efficacy for treating CHF, highlighting its potential as a therapeutic agent.
Context:
Chronic heart failure (CHF) is the common concern following myocardial infarction. Xijiaqi Formula (XJQ) effectively treats CHF clinically while the underlying mechanism remains unclarified.
Objective:
This study was designed to investigate the effect and mechanism of XJQ on CHF in rats following MI.
Materials And Methods:
UHPLC-Q-TOF-MS/MS was utilized to analyze the constituents of XJQ. Post-MI CHF was induced in rats by permanent ligation of the left anterior descending coronary artery. Cardiac function was assessed by echocardiogram and hemodynamic. Myocardial morphology, fibrosis, and ultrastructure were evaluated through HE staining, Masson staining, and transmission electron microscopy, respectively. Myocardial transcriptomics were employed to identify genes that may be altered in response to XJQ treatment. Consistently, XJQ inhibited TGF-β1-induced myofibroblast activation in vitro.
Results:
XJQ significantly improved cardiac function and structure, mitigating fibrosis, edema, and mitochondrial damage, while reducing key biomarkers (BNP, NT-proBNP, cTnT, Ang II). Transcriptomic analysis indicated that the differentially expressed genes influenced by XJQ were predominantly associated with extracellular matrix (ECM) remodeling. Notably, XJQ inhibited the upregulation of ECM proteins, including Adamts2, Fbln1, Itgbl1, and Ltbp3 mRNAs, as well as the proteins TGF-β1, P-Smad2/3, and MMP2. Additionally, in vitro experiments revealed that XJQ significantly suppressed the activation of myofibroblasts induced by TGF-β1.
Conclusions:
XJQ significantly attenuated the progression from MI to CHF by inhibiting fibroblast activation mediated by TGF-β1/Smads signaling. The molecular mechanisms underlying this effect appear to be intricately linked to its regulation of ECM remodeling proteins, specifically Adamts2, Itgbl1, Fbln1, and Ltbp3.
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