Down-regulation of miR-1/miR-133 Contributes to Re-expression of Pacemaker Channel Genes HCN2 and HCN4 in Hypertrophic Heart*

Abstract

Cardiac hypertrophy is characterized by electrical remolding with increased risk of arrhythmogenesis. Enhanced abnormal automaticity of ventricular cells contributes critically to hypertrophic arrhythmias. The pacemaker current I f , carried by the hyperpolarization-activated channels encoded mainly by the HCN2 and HCN4 genes in the heart, plays an important role in determining cardiac automaticity. Their expressions reportedly increase in hypertrophic and failing hearts, contributing to arrhythmogenesis under these conditions. We performed a study on post-transcriptional regulation of expression of HCN2 and HCN4 genes by microRNAs. We experimentally established HCN2 as a target for repression by the muscle-specific microRNAs miR-1 and miR-133 and established HCN4 as a target for miR-1 only. We unraveled robust increases in HCN2 and HCN4 protein levels in a rat model of left ventricular hypertrophy and in angiotensin II-induced neonatal ventricular hypertrophy. The up-regulation of HCN2/HCN4 was accompanied by pronounced reduction of miR-1/miR-133 levels. Forced expression of miR-1/miR-133 by transfection prevented overexpression of HCN2/HCN4 in hypertrophic cardiomyocytes. The serum-responsive factor protein level was found significantly decreased in hypertrophic hearts, and silencing of this protein by RNA interference resulted in increased levels of miR-1/miR-133 and concomitant increases in HCN2 and HCN4 protein levels. We conclude that down-regulation of miR-1 and miR-133 expression contributes to re-expression of HCN2/HCN4 and thereby the electrical remodeling process in hypertrophic hearts. Our study also sheds new light on the cellular function and pathological role of miR-1/miR-133 in the heart.

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“…Professor Yang provided evidence that miR-1 is overexpressed in patients with coronary artery dis-npg ease, and that overexpression of miR-1 in normal or infarcted rat hearts was found to exacerbate arrhythmogenesis. His data supported the suggestion that miRNAs are a potential anti-arrhythmic target [20].…”

Effect of MicroRNA Modulation on Bioartificial Muscle Function

“…17 Another pacing-related gene, HCN2, was a target of miR-133 and upregulated in the hypertrophic state associated with depressed miR-133. 18 On the basis of the established role for miR-133 in cardiac tissue function, we hypothesized that inhibiting this miRNA increases force production by skeletal muscle cells in threedimensional (3D) cultures by promoting differentiation. We previously showed that a collagen gel-based skeletal muscle system was successfully able to form mature, differentiated muscle in a 3D model.…”

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“…Arrhythmias arise due to heart disease or mutation in ion channel genes, however, miRNAs, such as miR-1 and miR-133 have been implicated to function in cardiac conduction system. The involvement of miR-1 in cardiac conductance was further confirmed by over expression studies in normal and infarcted rat hearts so as upregulation of miR-1 in individuals with coronary heart disease [145,146]. Myocardial vascularization subsequent MI needs signaling by angiogenic growth factors, such as vascular endothelial growth factor and fibroblast growth factor.…”