MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection.
OBJECTIVE
The present study was designed to investigate whether the beneficial effects of beta-blocker propranolol are related to regulation of microRNA miR-1.


RESULTS
We demonstrated that propranolol reduced the incidence of arrhythmias in a rat model of myocardial infarction by coronary artery occlusion. Overexpression of miR-1 was observed in ischaemic myocardium and strikingly, administration of propranolol reversed the up-regulation of miR-1 nearly back to the control level. In agreement with its miR-1-reducing effect, propranolol relieved myocardial injuries during ischaemia, restored the membrane depolarization and cardiac conduction slowing, by rescuing the expression of inward rectifying K(+) channel subunit Kir2.1 and gap junction channel connexin 43. Our results further revealed that the beta-adrenoceptor-cAMP-Protein Kinase A (PKA) signalling pathway contributed to the expression of miR-1, and serum response factor (SRF), which is known as one of the transcriptional enhancers of miR-1, was up-regulated in ischaemic myocardium. Moreover, propranolol inhibited the beta-adrenoceptor-cAMP-PKA signalling pathway and suppressed SRF expression.


CONCLUSIONS
We conclude that the beta-adrenergic pathway can stimulate expression of arrhythmogenic miR-1, contributing to ischaemic arrhythmogenesis, and beta-blockers produce their beneficial effects partially by down-regulating miR-1, which might be a novel strategy for ischaemic cardioprotection.
Lu
Yanjie
Y
Department of Pharmacology , Harbin Medical University, Harbin, Heilongjiang 150081, People's Republic of China.
Zhang
Yong
Y
Shan
Hongli
H
Pan
Zhenwei
Z
Li
Xuelian
X
Li
Baoxin
B
Xu
Chaoqian
C
Zhang
Bisi
B
Zhang
Fengmin
F
Dong
Deli
D
Song
Wuqi
W
Qiao
Guofen
G
Yang
Baofeng
B
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D015994:Incidence; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D011433:Propranolol / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; C542191:MIRN1 microRNA, rat; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D011943:Receptors, Adrenergic, beta; D026362:Serum Response Factor; D011433:Propranolol; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol