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MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection

Yanjie Lu , Yong Zhang , Hongli Shan , Zhenwei Pan , Xuelian Li , Baoxin Li , Chaoqian Xu , Bisi Zhang , Fengmin Zhang , Deli Dong , Wuqi Song , Guofen Qiao , Baofeng Yang
DOI: http://dx.doi.org/10.1093/cvr/cvp232 434-441 First published online: 6 July 2009

Abstract

Aims The present study was designed to investigate whether the beneficial effects of β-blocker propranolol are related to regulation of microRNA miR-1.

Methods and 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 β-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 β-adrenoceptor–cAMP–PKA signalling pathway and suppressed SRF expression.

Conclusion We conclude that the β-adrenergic pathway can stimulate expression of arrhythmogenic miR-1, contributing to ischaemic arrhythmogenesis, and β-blockers produce their beneficial effects partially by down-regulating miR-1, which might be a novel strategy for ischaemic cardioprotection.

  • Propranolol
  • Arrhythmia
  • MicroRNA
  • Ion channels
  • Myocardial infarction
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