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.

Background Ovarian cancer (OC) progression is an unmet medical challenge. Since omental metastases were palpated harder than their primary counterparts during cytoreductive surgery of patients with epithelial ovarian cancer (EOC), we were inspired to investigate OC progression from the perspective of biomechanics. Methods Atomic Force Microscope (AFM) was used to measure the Young’s modulus of tissues. The collagen-coated polyacrylamide hydrogel (PA gel) system was prepared to mimic the soft and stiff substrates in vitro. The effect of TAGLN was evaluated both in vitro and in vivo using transwell assay, immunofluorescence, western blot analysis and immunohistochemistry. Results We quantitatively confirmed that omental metastases were stiffer and more abundant in desmoplasia compared with paired primary tumors, and further demonstrated that matrix stiffness could notably regulate OC progression. Remarkably, TAGLN, encoding an actin cross-linking/gelling protein, was identified as a potent mechanosensitive gene that could form a regulation loop with Src activation reacting to environmental stiffness, thus mediating stiffness-regulated OC progression through regulating RhoA/ROCK pathway. Conclusions These data demonstrate that targeting extra-cellular matrix (ECM) stiffness could probably hamper OC progression, and of note, targeting TAGLN might provide promising clinical therapeutic value for OC therapy.

Background: Atrial tachycardia (AT) with cycle length (CL) alternans is a rare phenomenon. We aimed to identify the characteristics and precise mechanism of this special category of ATs by using an ultrahigh density mapping system. Methods: We identified 7 ATs with alternating CL in a total of 478 ATs from 2 institutions mapped with an ultrahigh density mapping system. Activation maps were performed for long CL (289±35 ms; mapping points, 21 520±11 103) and short CL (251±18 ms; mapping points,17 594±8059) separately. Results: We classified ATs with CL alternans into 2 types. Type 1: There existed 2 potential loops with different routes. CL alternans resulted from an intermittently 2:1 conducting block within the channel of the smaller loop. Type 2: CL alternans resulted from different conduction velocity through 2 closely spaced gaps within preexisting linear lesions. Catheter ablation successfully terminated all the 7 ATs. Conclusions: Ultrahigh density mapping provides an opportunity to delineate the precise mechanism of AT with CL alternans. Intermittent conduction block or slowing of a channel was essential for the maintenance of AT.

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