MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection
MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection
复制标题
普萘洛尔在心肌梗死大鼠模型中下调 MicroRNA-1：缺血性心脏保护的新机制
DOI：
10.1093/cvr/cvp232
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发表时间：
2009-12-01
影响因子：
10.8
通讯作者：
Yang, Baofeng
中科院分区：
文献类型：
--
作者：
Lu, Yanjie;Zhang, Yong;Yang, Baofeng
本研究旨在探讨β受体阻滞剂普萘洛尔的有益作用是否与调节microRNA miR-1有关。在缺血心肌中观察到miR-1的过表达，并且引人注目的是，给予普萘洛尔将miR-1的上调逆转至接近对照水平。与其减少miR-1的作用一致，普萘洛尔通过拯救内向整流K+通道亚基Kir2.1和间隙连接通道连接蛋白43的表达，减轻了缺血期间的心肌损伤，恢复了膜去极化和心脏传导减慢。我们的研究结果进一步揭示了β-肾上腺素受体-cAMP-蛋白激酶A（PKA）信号通路参与了miR-1的表达，而血清反应因子（SRF）作为miR-1的转录增强子之一，在缺血心肌中表达上调。结论：β-肾上腺素能通路可刺激miR-1的表达，促进缺血心肌的发生，β-受体阻滞剂通过下调miR-1发挥其作用，这可能是缺血心肌保护的一种新策略。
The present study was designed to investigate whether the beneficial effects of beta-blocker propranolol are related to regulation of microRNA miR-1.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.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.