期刊
BASIC RESEARCH IN CARDIOLOGY
卷 111, 期 6, 页码 -出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-016-0584-z
关键词
Atrial fibrillation; Macrophage-atrial myocyte interaction; Interleukin 1 beta; Quaking protein
资金
- National Natural Science Foundation of China [81170167, 81270002]
- Natural Science Foundation of Zhejiang Province [LZ16H020001]
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-1 beta), which inhibited atrial myocyte quaking protein (QKI) expression. IL-1 beta knockout in macrophages restored the LPS-stimulated macrophage-induced inhibition of QKI and CACNA1C (alpha 1C 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-1 beta, further inhibiting QKI expression in atrial myocytes, which contributed to ICa-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.
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