let-7e replacement yields potent anti-arrhythmic efficacy via targeting beta 1-adrenergic receptor in rat heart

Beta-adrenoceptor (β-ar) exerts critical regulation of cardiac function. micrornas (mirnas) are potentially involved in a variety of biological and pathological processes. this study aimed to investigate the role of mirna let-7e in the up-regulation of β1-ar and arrhythmogenesis in acute myocardial infarction (ami) in rats. β1-ar expression was significantly up-regulated and let-7a,c,d,e and i were markedly down-regulated in the infarcted heart after 6 and 24 hrs myocardial infarction. forced expression of let-7e suppressed β1-ar expression at the protein level,without affecting β1-ar mrna level,in neonatal rat ventricular cells (nrvcs). silencing of let-7e by let-7e antisense inhibitor (amo-let-7e) enhanced β1-ar expression at the protein level in nrvcs. administration of the lentivirus vector containing precursor let-7e (len-pre-let-7e) significantly inhibited β1-ar expression in rats,whereas len-amo-let-7e up-regulated β1-ar relative to the baseline control level,presumably as a result of depression of tonic inhibition of β1-ar by endogenous let-7e. len-negative control (len-nc) did not produce significant influence on β1-ar expression. len-pre-let-7e also profoundly reduced the up-regulation of β1-ar induced by ami and this effect was abolished by len-amo-let-7e. importantly,len-pre-let-7e application significantly reduced arrhythmia incidence after ami in rats and its anti-arrhythmic effect was cancelled by len-amo-let-7e. notably,anti-arrhythmic efficacy of len-pre-let-7e was similar to propranolol,a non-selective β-ar blocker and metoprolol,a selective β1-ar blocker. down-regulation of let-7e contributes to the adverse increase in β1-ar expression in ami and let-7e supplement may be a new therapeutic approach for preventing adverse β1-ar up-regulation and treating ami-induced arrhythmia. © 2014 the authors.