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 (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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-016-0584-z) contains supplementary material, which is available to authorized users.

Fisetin Alleviates Atrial Inflammation, Remodeling, and Vulnerability to Atrial Fibrillation after Myocardial Infarction

“…Enlarged LAD and LVEDD, and reduced LVEF and LVFS, were presented in MI group. Fisetin antagonizes macrophage-mediated inflammation in LA tissue post-MI: Because macrophages play a critical role in inflammation and AF, 11,25) we performed immunofluorescence on LA sections by examining macrophage specific marker (CD68) at 28 days post-MI. Compared with the sham group, the number of CD68-positive (CD68 + ) macrophages infiltrating the LA was increased in the MI group.…”

“…10) Atrial fibrosis that is linked, not only to stimulation of myocytes and fibroblasts, but also to the activation status of inflammatory cells, has also emerged as an important pathogenic contributor of AF initiation, progression, and maintenance by reentry activity and slow conduction. 7,11) Inhibition of myocardial fibrosis and oxidative stress can reduce AF occurrence. 12) These causes suggests that suppressing the process of atrial inflammation and fibrosis is a potential therapeutic target of AF.…”

Myeloid cells in cardiovascular organs

“…At this point, it is less clear whether a changed macrophage number or altered phenotype of macrophages contribute to conduction abnormalities. First small studies associate macrophage numbers with atrial fibrillation in humans , and macrophage depletion experiments suggest that the cells may be causally involved. Clearly, more work is needed in this emerging area of immuno‐electrophysiology, given that there are many unknowns but pressing clinical needs, especially for atrial and ventricular fibrillation.…”

Synergistic Research Between the Center of Arrhythmia Research and the Michigan Biology of Cardiovascular Aging at the University of Michigan

“…Clinical studies have associated several circulating inflammatory mediators, including C-reactive protein (CRP), interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, immune complement activation and galectin-3 with AF. 5, 11 Macrophages and neutrophils may contribute to AF by infiltrating atrial tissue, releasing reactive oxygen species (ROS), producing inflammatory cytokines, metalloproteinases or myeloperoxidases. 12 Aging is associated with increased inflammation, evidenced by increased presence of circulating inflammatory cytokines., although the mechanisms underlying this phenomenon are not clear.…”