Cross-talk Between Macrophages And Atrial Myocytes In Atrial Fibrillation

Atrial fibrillation(AF)is the most common cardiac arrhythmia.Previous studies have demonstrated that inflammation plays an important role in AF initiation and maintenance.Recently,increased macrophages infiltration was found in the atria in AF patients.However,the phenotype and functions of these macrophages remained unknown.To address these questions,we carried out the following research:First,we collected and analyzed the right atrial appendages(RAA)from AF and sinus rhythm patients.We found that there were increased macrophages in the RAA in AF patients.These macrophages were mainly pro-inflammatory(iNOS positive while Argl negative).Co-culture macrophages with tachypaced mouse atrial myocytes(HL-1 cells)also induced macrophages pro-inflammatory polarization.Meanwhile,LPS-stimulated macrophages induced the atrial electrical remodeling,evidenced by the increased incidence of AF,the decreased of effective refractory period and L type calcium currents.Using Clodronate Liposomes to deplete the atrial pro-inflanmatory macrophages relieved LPS induced electrical remodeling,further confirming the role of pro-inflammatory macrophages played in AF.In terms of the molecular mechanism,we found that the pro-inflammatory macrophages induced atrial electrical remodeling was mediated by the secretion of IL-1β.The pro-inflammatory macrophages secreted IL-1(3,which further induced the down regulation of QKI expression in atrial myocytes.On the contrary,IL-1β knockout in pro-inflammatory macrophages abolished the pro-inflammatory macrophages induced inhibition of QKI expression,further confirming that the QKI expression in atrial myocytes was mediated by the secretion of IL-1β in macrophages.Moreover,we found that over expression of QKI up regulated the binding ability between QKI and CACNA1C mRNA(the α1C subunit of L-type calcium channel)as well as the CACNA1C expression and L-type calcium currents.On the contrary,QKI knockout in atrial myocytes inhibited the CACNA1C expression.Finally,to investigate the transcriptional regulation of QKI,we performed the transcription factors activation profiling plate assay and found that the special AT-rich sequence binding protein 1(SATB1)activated QKI transcription.In conclusion,we found that AF promoted macrophages pro-inflammatory polarization,while pro-inflammatory macrophages down regulated the QKI expression in atrial myocytes by IL-1β secretion,which further inhibited the binding ability between QKI and CACNA1C mRNA and the L-type calcium currents.Our study uncovered the interaction between macrophages and atrial myocytes in AF and provided QKI as a novel therapy target.