Control of cardiac excitability and arrhythmias by microRNAs

Recent studies revealing the important roles of microRNAs（miRNAs） in regulating expression of ion channel genes have opened up a research field for extending and deepening our investi- gation into the cardiac excitability and the associated arrhythmogenesis.Cardiac excitability,the fundamental property of the cardiac myocytes,defines the cardiac conduction,repolarization,automaticity,intracellular calcium handling,and their regional heterogeneity. Our previous and ongoing studies and the work from other laboratories have demonstrated the significant involvement of miRNAs in regulating every aspects of cardiac excitability.We have found earlier that the muscle-specific miRNA miR-1 boosts up the arrhythmogenic potential through targeting gap junction channel connexin 43 in myocardial infarction.A subsequent study revealed that miR-1 can also cause arrhythmias by impairing Ca2+ handling by targeting phosphatase.We then identified another muscle-specific miRNA miR-133 promotes abnormal QT prolongation by repressing HERG K+ channel expression in diabetic cardiomyopathy. Subsequently,we discovered that both miR- 1 and miR-133 are involved in the reexpression of pacemaker channels HCN2/HCN4 to enhance abnormal automaticity in cardiac hypertrophy.Recently, we further identified miR-328 as an important determinant for atrial fibrillation（AF） and the associated adverse atrial electrical remodeling via targeting L-type Ca2+ channels.While all the above-mentioned miRNAs are proarrhythmic,we have newly identified for the first time a natural antiarrhythmic miRNA miR-26.We found that all three members of the miR-26 family is downregulated in their expression in AF tissues and this downregulation increases AF vulnerability as a result of removal of an endogenous antiarrhythmic factor.miR-26 downregulation shortens atrial action potential favoring AF by increasing inward rectifier K+ current（IK1） density. This is caused by an upregulation of Kir2.1 K+ channel subunit due to derepression of its encoding gene KCNJ2 as we have validated KCNJ2 as a target gene for miR-26.Administration of a LNA-modified antimiR-26 antisense through tail vein injection increases AF vulnerability as indicated by increased number of mice with AF induction by intracardiac pacing.And this effect is blunted by co-injection of either an adenovirus vector carrying miR-26 precursor sequence or a LNA-modified miR-26 mimic to specifically target KCNJ2.We further discovered that the activity of NFAT transcription factor is enhanced in AF which represses the transcription of miR-26. We characterized the promoter region of the host genes of all three members of the miR-26 miRNA family and identified a common cis-acting element for NFAT binding.Thus,our study unraveled a novel miRNA signaling pathway AF NFAT miR-26 KC-NJ2 /Kir2.1/IK1 AF as a positive feedback loop favoring AF and the remodeling process.