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 β(1) -AR and arrhythmogenesis in acute myocardial infarction (AMI) in rats. β(1) -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 β(1) -AR expression at the protein level, without affecting β(1) -AR mRNA level, in neonatal rat ventricular cells (NRVCs). Silencing of let-7e by let-7e antisense inhibitor (AMO-let-7e) enhanced β(1) -AR expression at the protein level in NRVCs. Administration of the lentivirus vector containing precursor let-7e (len-pre-let-7e) significantly inhibited β(1) -AR expression in rats, whereas len-AMO-let-7e up-regulated β(1) -AR relative to the baseline control level, presumably as a result of depression of tonic inhibition of β(1) -AR by endogenous let-7e. Len-negative control (len-NC) did not produce significant influence on β(1) -AR expression. Len-pre-let-7e also profoundly reduced the up-regulation of β(1) -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 β(1) -AR blocker. Down-regulation of let-7e contributes to the adverse increase in β(1) -AR expression in AMI and let-7e supplement may be a new therapeutic approach for preventing adverse β(1) -AR up-regulation and treating AMI-induced arrhythmia.
Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education; State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang, China.
Xin
X
Li
Baoqiu
B
Wang
Hairong
H
Cui
Yue
Y
Du
Yang
Y
Song
Lei
L
Yang
Qi
Q
Zhang
Fei
F
Sun
Dan
D
Luo
Chaoqian
C
Xu
Wenfeng
W
Chu
Yanjie
Y
Lu
Baofeng
B
Yang
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006339:Heart Rate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020413:3' Untranslated Regions; D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D035683:MicroRNAs; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; C487931:mirnlet7 microRNA, human
acute myocardial infarction; anti-arrhythmia; let-7e; β1-AR