title: Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p.
abstract: The SCN5A gene encodes cardiac sodium channel Nav1.5 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/Nav1.5 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 Nav1.5 as well as peak sodium current density INa generated by Nav1.5. 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/Nav1.5. These results demonstrate an important post-transcriptional role of miR-192-5p in post-transcriptional regulation of Nav1.5, 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 INa.
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, PR China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, PR China.
authors.forename: Shaopeng
authors.initials: S
authors.lastname: Zhan
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Mengchen
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, PR China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, PR China.
authors.forename: Yuxi
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Molecular Medicine, CCLCM, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China; Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Molecular Medicine, CCLCM, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. Electronic address: qkwang@hust.edu.cn.
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Xiamen, PR China. Electronic address: huangzhengrong@xmu.edu.cn.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Huang
keywords: Atrial fibrillation; Cardiac sodium channel Na(v)1.5; MiR-192-5p; MicroRNA; SCN5A