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The SCN5A gene encodes cardiac sodium channel Na v 1.5 and causes lethal ventricular arrhythmias/sudden death and atrial fibrillation (AF) when mutated. MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, and involved in the pathogenesis of many diseases. However, little is known about the regulation of SCN5A by miRNAs. Here we reveal a novel post-transcriptional regulatory mechanism for expression and function of SCN5A /Na v 1.5 via miR-192-5p . Bioinformatic analysis revealed that the 3′-UTR of human and rhesus SCN5A , but not elephant, pig, rabbit, mouse, and rat SCN5A , contained a target binding site for miR-192-5p and dual luciferase reporter assays showed that the site was critical for down-regulation of human SCN5A . With Western blot assays and electrophysiological studies, we demonstrated that miR-192-5p significantly reduced expression of SCN5A and Na v 1.5 as well as peak sodium current density I Na generated by Na v 1.5. Notably, in situ hybridization, immunohistochemistry and real-time qPCR analyses showed that miR-192-5p was up-regulated in tissue samples from AF patients, which was associated with down-regulation of SCN5A /Na v 1.5. These results demonstrate an important post-transcriptional role of miR-192-5p in post-transcriptional regulation of Na v 1.5, reveal a novel role of miR-192-5p in cardiac physiology and disease, and provide a new target for novel miRNA-based antiarrhythmic therapy for diseases with reduced I Na . [ABSTRACT FROM AUTHOR]

Hypoxia stimulates angiogenesis under a variety of pathological conditions, including malignant tumors by inducing expression of angiogenic factors such as VEGFA. Surprisingly, here we report significant association between down-regulation of a new angiogenic factor AGGF1 and high-grade urothelial carcinoma. The proportion of strong AGGF1 expression cases was significantly lower in the high-grade urothelial carcinoma group than that in the low-grade urothelial carcinoma group (P =1.40×10−5) or than that in the normal urothelium tissue group (P =2.11×10−4). We hypothesized that tumor hypoxia was responsible for differential expression of the AGGF1 protein in low- and high-grade urothelial carcinomas, and therefore investigated the molecular regulatory mechanism for AGGF1 expression under hypoxia. Under hypoxic conditions, AGGF1 protein levels declined without any change in mRNA levels and protein stability. Hypoxia-induced down-regulation of AGGF1 was mediated by miR-27a. Overexpression of miR-27a suppressed AGGF1 expression through translational inhibition, but not by RNA degradation. Moreover, the hypoxia-induced decrease of AGGF1 expression disappeared after miR-27a expression was inhibited. Furthermore, down-regulation of AGGF1 reduced hypoxia-induced apoptosis in cancer cells. Taken together, the results of this study indicate that (1) hypoxia down-regulates expression of the AGGF1 protein, but not AGGF1 mRNA, by inducing expression of miR-27a; (2) Down-regulation of AGGF1 had an apparent protective role for cancer cells under hypoxia; (3) Down-regulation of the AGGF1 protein confers a significant risk of high-grade human urothelial bladder carcinoma. [ABSTRACT FROM AUTHOR]