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

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Abstract

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.

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