title: Cross-talk between macrophages and atrial myocytes in atrial fibrillation.
abstract: 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 (ICa-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 ICa-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 ICa-Ldownregulation. Our study demonstrates a novel molecular mechanism underlying the pathogenesis and progression of AF and suggests that QKI is a potential therapeutic target.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Zewei
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Dongchen
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Cardiothoracic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China. zlrylnn@126.com.
authors.forename: Liangrong
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology*; D064752:Atrial Remodeling / Q000502:physiology; D015153:Blotting, Western; D002450:Cell Communication / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004285:Dogs; D005260:Female; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C490832:QKI protein, human; C098217:Qk protein, mouse; D016601:RNA-Binding Proteins
keywords: Atrial fibrillation; Interleukin 1 beta; Macrophage-atrial myocyte interaction; Quaking protein