Abstract
Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein–protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl2) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.
Highlights
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia with significant health and socioeconomic impact [1]
The expression validation of CXCL12 and CXCR4 was completely consistent with the results of our bioinformatics analysis, which suggested the excessively activated CXCL12/CXCR4 axis may contribute to the development of AF
gene ontology (GO) functionenrichment analysis resulted in 134 items, of which biological processes (BP) accounted for 97, cell components (CC) for 18, and molecular function (MF) for 19 items (Supplementary file 6A)
Summary
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia with significant health and socioeconomic impact [1]. Apart from worsening patient quality of life, AF is associated with stroke, newonset heart failure, dementia, and increased mortality [2]. Despite significant effort has been done to clarify the molecular and cellular mechanisms underlying AF, the advancement is obstructed by the reality that AF is a complex arrhythmia. New drugs specially designed for the therapy of AF remain suboptimal and patients, especially with persistent AF, have to depend on antique antiarrhythmic drugs, such as amiodarone, sotalol, propafenone, and flecainide that have limited efficacy and significant side effects [3]. Numerous researches have suggested that AF cases in the general population have a significant genetic component, even beyond traditional risk factors [4, 5]. Exploring transcriptome data with bioinformatics analysis may be detect some potential mechanisms of AF to provide novel mechanism-targeting therapies and aid in future clinical studies [6]
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