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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 Pathological cardiac hypertrophy is a major contributor of heart failure (HF), which seriously threatens human’s health world widely. Deregulation of m6A RNA methylation, and m6A methyltransferases and de-methyltransferases have been demonstrated to act essential roles in cardiac hypertrophy and HF. Here, we studied the potential roles and its underlying mechanisms of m6A Reader YTHDF proteins in HF. In this study, we constructed HF mouse model by transverse aortic constriction surgery. Primary cardiomyocytes were isolated and stimulated with isoproterenol (ISO) or phenylephrine (PHE) to induce myocardial hypertrophy. Results Through single-cell RNA-seq analysis, immunofluorescent staining, HE staining, Western blotting, and real time-PCR detections, we found that YTHDF2 mRNA and protein level, but not YTHDF1 or YTHDF3, was significantly increased during HF development. YTHDF2 overexpression could efficiently alleviate cardiac hypertrophy. Furthermore, through immunoprecipitation accompanied with mass spectrometry analysis, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that ISO stimulation did not evidently affect YTHDF2-interacting proteins. However, ISO or PHE stimulation significantly increased YTHDF2 protein interacting with Myh7 (beta-myosin heavy chain) mRNA, an important cardiac hypertrophy marker, in an m6A-dependent manner. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2 on cardiac hypertrophy. Finally, we found that ISO or PHE stimulation promoted YTHDF2 protein expression through enhancing Ythdf2 mRNA stability in an m6A-dependent manner in cardiomyocytes. Conclusions Overall, our results indicate that the m6A Reader YTHDF2 suppresses cardiac hypertrophy via Myh7 mRNA decoy in an m6A-dependent manner. This study highlights the functional importance of YTHDF2-dependent cardiac m6A mRNA regulation during cardiac hypertrophy, and provides a novel mechanistic insight into the therapeutic mechanisms of YTHDF2.

The mevalonate pathway is essential for cholesterol biosynthesis. Previous studies have suggested that the key enzyme in this pathway, farnesyl diphosphate synthase (FDPS), regulates the cardiovascular system. We used human samples and mice that were deficient in cardiac FDPS (c-Fdps À/À mice) to investigate the role of FDPS in cardiac homeostasis. Cardiac function was assessed using echocardiography. Left ventricles were examined and tested for histological and molecular markers of cardiac remodeling. Our results showed that FDPS levels were downregulated in samples from patients with cardiomyopathy. Furthermore, c-Fdps À/À mice exhibited cardiac remodeling and dysfunction. This dysfunction was associated with abnormal activation of Ras and Rheb, which may be due to the accumulation of geranyl pyrophosphate. Activation of Ras and Rheb stimulated downstream mTOR and ERK pathways. Moreover, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in c-Fdps À/À mice. These results indicate that FDPS plays an important role in cardiac homeostasis. Deletion of FDPS stimulates the downstream mTOR and ERK signaling pathways, resulting in cardiac remodeling and dysfunction.

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Intrathoracic goiter is commonly located in the anterior mediastinum. Here we report a case of a 58-year-old Chinese male in whom we successfully removed the intrathoracic goiter and eased his dyspnea by a right posterolateral thoracotomy approach. Posterior mediastinal thyroid goiter with mediastinal compressive symptoms is an indication of surgery.

Background Observational studies suggest that sleep disturbances are commonly associated with schizophrenia. However, it is uncertain whether this relationship is causal. To investigate the bidirectional causal relation between sleep traits and schizophrenia, we performed a two-sample bidirectional Mendelian randomization (MR) study with the fixed effects inverse-variance weighted (IVW) method. Methods As genetic variants for sleep traits, we selected variants from each meta-analysis of genome-wide association studies (GWASs) conducted using data from the UK Biobank (UKB). Results We found that morning diurnal preference was associated with a lower risk of schizophrenia, while long sleep duration and daytime napping were associated with a higher risk of schizophrenia. Multivariable MR analysis also showed that sleep duration was associated with a higher risk of schizophrenia after adjusting for other sleep traits. Furthermore, genetically predicted schizophrenia was negatively associated with morning diurnal preference and short sleep duration and was positively associated with daytime napping and long sleep duration. Conclusions Therefore, sleep traits were identified as a potential treatment target for patients with schizophrenia.

Lung cancer is the leading cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) promotes lung cancer progression and metastasis, especially in lung adenocarcinoma. Sex determining region Y-box protein 5 (SOX5) is known to stimulate the progression of various cancers. Here, we used immunohistochemical analysis to reveal that SOX5 levels were increased in 90 lung adenocarcinoma patients. The high SOX5 expression in lung adenocarcinoma and non-tumor counterparts correlated with the patients’ poor prognosis. Inhibiting SOX5 expression attenuated metastasis and progression in lung cancer cells, while over-expressing SOX5 accelerated lung adenocarcinoma progression and metastasis via EMT. An in vivo zebrafish xenograft cancer model also showed SOX5 knockdown was followed by reduced lung cancer cell proliferation and metastasis. Our results indicate SOX5 promotes lung adenocarcinoma tumorigenicity and can be a novel diagnosis and prognosis marker of the disease.