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Dihydrolycorine Attenuates Cardiac Fibrosis and Dysfunction by Downregulating Runx1 following Myocardial Infarction
Tingjuan Ni1, Xingxiao Huang2, Sunlei Pan3
1Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Insights
Dihydrolycorine effectively inhibits Runx1, preventing adverse cardiac remodeling and improving heart function after myocardial infarction (MI). This novel therapeutic approach targets Runx1 to combat pathological ventricular remodeling and heart failure post-MI.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Adverse cardiac remodeling post-acute myocardial infarction (MI) leads to heart failure, posing a significant clinical challenge.
- Current interventions struggle to fully prevent pathological ventricular remodeling, necessitating novel therapeutic strategies.
- Runx1 was identified as a key differentially expressed gene in MI models, linked to decreased cardiac function.
Purpose of the Study:
- To investigate the role of Runx1 in post-MI cardiac remodeling.
- To identify and evaluate dihydrolycorine as a potential therapeutic agent targeting Runx1.
- To elucidate the mechanism by which dihydrolycorine mitigates adverse cardiac remodeling.
Main Methods:
- RNA-sequencing analysis of MI rat models to identify differentially expressed genes.
- In vivo and in vitro experiments using dihydrolycorine treatment in MI models and cardiomyocytes.
- Western blotting, immunofluorescence staining, and wheat germ agglutinin staining to assess cardiac remodeling markers.
- Molecular docking, binding modeling, and pull-down assays to determine Runx1-dihydrolycorine interactions.
- Gene silencing (Ad-sh-Runx1) to validate Runx1's role.
Main Results:
- Increased Runx1 expression correlated with reduced cardiac contractile function post-MI.
- Dihydrolycorine treatment downregulated fibrotic genes (collagen I, TGFβ, p-smad3), reduced apoptosis (Bax), and increased survival (Bcl-2).
- Dihydrolycorine improved cardiac function (LVEF, LVSF, LVESD, LVEDD), rescued cardiomyocyte hypertrophy, and normalized connexin 43 and α-SMA expression.
- Molecular studies confirmed dihydrolycorine binds to Runx1, inhibiting its activity.
- Runx1 knockdown abolished dihydrolycorine's cardioprotective effects and disrupted cardiomyocyte electrophysiology.
Conclusions:
- Dihydrolycorine effectively inhibits adverse cardiac remodeling after MI by downregulating Runx1 expression and activity.
- Targeting Runx1 with dihydrolycorine presents a promising novel therapeutic strategy for preventing heart failure post-MI.
- This study highlights the therapeutic potential of dihydrolycorine in managing pathological ventricular remodeling.
Abstract:
In spite of early interventions to treat acute myocardial infarction (MI), the occurrence of adverse cardiac remodeling following heart failure due to acute MI remains a clinical challenge. Thus, there is an increasing demand for the development of novel therapeutic agents capable of inhibiting the development of pathological ventricular remodeling. RNA-seq data analysis of acute MI rat models from GEO revealed that Runx1 was the most differentially expressed MI-related gene. In this study, we demonstrated that increased Runx1 expression under pathological conditions results in decreased cardiac contractile function. We identified dihydrolycorine, an alkaloid lycorine, as a promising inhibitor of Runx1. Our results showed that treatment with this drug could prevent adverse cardiac remodeling, as indicated by the downregulation of fibrotic genes using western blotting (collagen I, TGFβ, and p-smad3), downregulation of the apoptosis gene Bax, upregulation of the apoptosis gene Bcl-2, and improved cardiac functions, such as LVEF, LVSF, LVESD, and LVEDD. Additionally, dihydrolycorine treatment could rescue cardiomyocyte hypertrophy as demonstrated by wheat germ agglutinin staining, increased expression levels of the punctuate gap junction protein connexin 43, and decreased α-SMA expression, resulting in cardiomyocyte fibrosis in immunofluorescence staining. Molecular docking, binding modeling, and pull-down assays were used to identify potential dihydrolycorine-binding sites in Runx1. When Ad-sh-Runx1 was transfected into hypoxia-cardiomyocytes or injected into the hearts of MI rats, the cardioprotective effects of dihydrolycorine were abolished, and the normal electrophysiological activity of cardiomyocytes was disrupted. Taken together, the results of the present study indicate that dihydrolycorine may inhibit adverse cardiac remodeling after MI through the reduction of Runx1, suggesting that dihydrolycorine-mediated-Runx1 regulation might represent a novel therapeutic approach for adverse cardiac remodeling after MI.
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