Over-expression of microRNA-1 causes arrhythmia by disturbing intracellular trafficking system

Abstract

Dysregulation of intracellular trafficking system plays a fundamental role in the progression of cardiovascular disease. Up-regulation of miR-1 contributes to arrhythmia, we sought to elucidate whether intracellular trafficking contributes to miR-1-driven arrhythmia. By performing microarray analyses of the transcriptome in the cardiomyocytes-specific over-expression of microRNA-1 (miR-1 Tg) mice and the WT mice, we found that these differentially expressed genes in miR-1 Tg mice were significantly enrichment with the trafficking-related biological processes, such as regulation of calcium ion transport. Also, the qRT-PCR and western blot results validated that Stx6, Braf, Ube3a, Mapk8ip3, Ap1s1, Ccz1 and Gja1, which are the trafficking-related genes, were significantly down-regulated in the miR-1 Tg mice. Moreover, we found that Stx6 was decreased in the heart of mice after myocardial infarction and in the hypoxic cardiomyocytes, and further confirmed that Stx6 is a target of miR-1. Meanwhile, knockdown of Stx6 in cardiomyocytes resulted in the impairments of PLM and L-type calcium channel, which leads to the increased resting ([Ca2+]i). On the contrary, overexpression of Stx6 attenuated the impairments of miR-1 or hypoxia on PLM and L-type calcium channel. Thus, our studies reveals that trafficking-related gene Stx6 may regulate intracellular calcium and is involved in the occurrence of cardiac arrhythmia, which provides new insights in that miR-1 participates in arrhythmia by regulating the trafficking-related genes and pathway.

New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

“…Indeed, premature upregulation of miR-1 during embryogenesis inhibits proliferation of PF precursors, possibly through downregulation of the cyclin dependent kinase Cdk6 which by consequence results in an upregulation of the pocket proteins. Overexpression of miR1 also perturbed Ca2+ handling in PF via its inhibiting effects on the SNARE protein Syntaxin 6 (Stx6), involved in cellular trafficking [96]. Thus, miR1 overexpressing mice present various conductive defects such as tachycardia, arrhythmia, slow atrioventricular conduction (long PR) or AVB, and slow ventricular conduction (long QRS) [97].…”

This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy

“…There are few direct connections between Mon1-Ccz1 and human disease, though autophagy is central to many aspects of human health, including cancer and neuronal/cardiac ischemia ( Choi et al, 2013 ). However, Ccz1 is post-transcriptionally downregulated by miR-1, a microRNA that causes cardiac arrhythmias when overexpressed ( Yang et al, 2007 ; Su et al, 2017 ). This suggests that Mon1-Ccz1-dependent autophagy or mitophagy suppresses arrhythmias, perhaps by removing damaged mitochondria that generate aberrant intracellular ion fluxes in cardiomyocytes ( Brown and O’Rourke, 2010 ).…”

Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection

“…Association between miR-1 up-regulation and the development of cardiac arrhythmias have since been later documented in other studies both in animals [85,86] and humans [87]. Mechanisms potentially involved in miR-1-mediated arrhythmogenesis include processes such as enhanced Ca 2+ release [114], dissociation of phosphatase activity from RyR2 complex [85], altered expression of K + channels [84,115], disturbed intracellular trafficking system [116], or altered expression of connexin-43 (Cx43) [84]. However, the exact mechanism by which miR-1 contributes to arrhythmogenesis is still to be elucidated.…”