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.
Highlights
Adverse cardiac remodeling after myocardial infarction (MI) results in the development of heart failure, which is a leading cause of high mortality rates [1, 2]
The differentially expressed MI-related gene profiles of the infarct area were screened from the GSE1146395 dataset obtained from the Gene Expression Omnibus (GEO) database based on a threshold of ∣log 2FC ∣ >2:0, and adj:P:Val < 0:05
We identified that the cardiac functional protein, punctuate gap junction protein connexin 43 was rescued by dihydrolycorine treatment in hypoxia-cardiomyocytes in proximity to the plasma membrane according to immunofluorescent staining results (Figures 5(f) and 5(g))
Summary
Adverse cardiac remodeling after myocardial infarction (MI) results in the development of heart failure, which is a leading cause of high mortality rates [1, 2]. Acute coronary artery blockage after MI can lead to the cardiomyocyte death and eccentric hypertrophy of surviving cardiomyocytes and initiate a reparative process involving the deposition of fibrillar collagens in infarcted and noninfarcted areas This subsequently causes myocardial fibrosis, which induces harmful cardiac remodeling and cardiac dysfunction [3,4,5]. Dihydrolycorine (C16H19NO4), an alkaloid lycorine, is obtained by contact hydrogenation from lycoris, a derivative of the Lycoraceae family member pyrrophenthridine [6]. It has diverse biological functions, including antitumor [7,8,9], neuroprotective [10], antiosteoporosis [11], antiviral [12], and anti-inflammatory [13] functions, as reported by various clinical studies.
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