Cross-talk between macrophages and atrial myocytes in atrial fibrillation

• Published in: Basic research in cardiology 2016-11, Vol.111 (6), p.63-19, Article 63
• Main Authors: Sun, Zewei, Zhou, Dongchen, Xie, Xudong, Wang, Shuai, Wang, Zhen, Zhao, Wenting, Xu, Hongfei, Zheng, Liangrong
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Atrial Remodeling - physiology; Blotting, Western; Cardiology; Cell Communication - physiology; Chromatin Immunoprecipitation; Dogs; Female; Heart Atria - metabolism; Humans; Macrophage Activation - physiology; Macrophages - metabolism; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Middle Aged; Myocytes, Cardiac - metabolism; Original Contribution; Patch-Clamp Techniques; Rats; Real-Time Polymerase Chain Reaction; RNA-Binding Proteins - metabolism
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-016-0584-z

Increased macrophage accumulation occurs in the atria of patients with atrial fibrillation (AF). However, the phenotype and functions of the macrophages in AF remain unclear. We investigated the macrophage-atrial myocyte interaction in AF patients and found that the increased macrophages were mainly pro-inflammatory macrophages (iNOS + , Arg1 − ). Tachypacing of HL-1 atrial myocytes also led to pro-inflammatory macrophage polarization. In addition, lipopolysaccharide (LPS)-stimulated pro-inflammatory macrophages-induced atrial electrical remodeling, evidenced by increased AF incidence and decreased atrial effective refractory period and L-type calcium currents ( I Ca-L ) in both canine and mouse AF models. Depletion of macrophages relieved LPS-induced atrial electrical remodeling, confirming the role of pro-inflammatory macrophages in the pathogenesis of AF. We also found that the effect of LPS-stimulated macrophages on atrial myocytes was mediated by secretion of interleukin 1 beta (IL-1β), which inhibited atrial myocyte quaking protein (QKI) expression. IL - 1β knockout in macrophages restored the LPS-stimulated macrophage-induced inhibition of QKI and CACNA1C (α1C subunit of L-type calcium channel) in atrial myocytes. Meanwhile, QKI overexpression in atrial myocytes restored the LPS-stimulated macrophage-induced electrical remodeling through enhanced binding of QKI to CACNA1C mRNA, which upregulated the expression of CACNA1C as well as I Ca-L . In contrast, QKI knockout inhibited CACNA1C expression. Finally, using transcription factor activation profiling plate array and chromatin immunoprecipitation, we revealed that special AT-rich sequence binding protein 1 activated QKI transcription. Taken together, our study uncovered the functional interaction between macrophages and atrial myocytes in AF. AF induced pro-inflammatory macrophage polarization while pro-inflammatory macrophages exacerbated atrial electrical remodeling by secreting IL-1β, further inhibiting QKI expression in atrial myocytes, which contributed to I Ca-L downregulation. Our study demonstrates a novel molecular mechanism underlying the pathogenesis and progression of AF and suggests that QKI is a potential therapeutic target.