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.