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. Micro RNAs (mi RNAs) are potentially involved in a variety of biological and pathological processes. This study aimed to investigate the role of mi RNA 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 m RNA 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. [ABSTRACT FROM AUTHOR]