Tanshinone IIA protects against sudden cardiac death induced by lethal arrhythmias via repression of microRNA-1
Tanshinone IIA protects against sudden cardiac death induced by lethal arrhythmias via repression of microRNA-1
复制标题
丹参酮 IIA 通过抑制 microRNA-1 预防致命性心律失常引起的心脏性猝死
DOI：
10.1111/j.1476-5381.2009.00377.x
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Yang, Baofeng
中科院分区：
文献类型：
--
作者：
Shan, Hongli;Li, Xuelian;Yang, Baofeng
背景与目的：丹参酮IIA是以丹参为基础的中药活性成分，通过抑制缺血性心律失常降低心源性猝死。然而，其抗心律失常作用的机制尚不清楚。实验方法：采用结扎大鼠左冠状动脉前降支致心肌梗死模型。在心肌梗死前（7天）和后（3个月）每日给予丹参酮IIA或奎尼丁；心电图监测心电活动。采用全细胞膜片钳技术测量大鼠离体心室肌细胞内向整流K+电流（I-K1）。Western blot检测Kir2.1和血清反应因子（SRF）水平，实时RT-PCR检测microRNA-1 （miR-1）水平。关键结果：丹参酮IIA降低心肌梗死后3个月大鼠急性心肌缺血致心律失常发生率和死亡率，丹参酮IIA恢复心肌梗死后大鼠心室肌细胞I-K1电流密度和Kir2.1蛋白的下降，而奎尼丁进一步抑制I-K1/Kir2.1。MiR-1在MI中上调，可能是由于MiR-1基因的转录激活因子SRF的增加，导致Kir2.1降低。丹参酮IIA治疗可预防心肌梗死后SRF升高和miR-1升高，而奎尼丁则没有。结论和意义：丹参酮IIA抑制缺血性心律失常和心脏死亡率的部分原因可能是miR-1的下调和Kir2.1的恢复。这些发现支持了miR-1可能是预防缺血性心律失常的潜在治疗靶点的建议。
Background and purpose:Tanshinone IIA is an active component of a traditional Chinese medicine based on Salvia miltiorrhiza, which reduces sudden cardiac death by suppressing ischaemic arrhythmias. However, the mechanisms underlying the anti-arrhythmic effects remain unclear.Experimental approach:A model of myocardial infarction (MI) in rats by ligating the left anterior descending coronary artery was used. Tanshinone IIA or quinidine was given daily, before (7 days) and after (3 months) MI; cardiac electrical activity was monitored by ECG recording. Whole-cell patch-clamp techniques were used to measure the inward rectifying K+ current (I-K1) in rat isolated ventricular myocytes. Kir2.1 and serum response factor (SRF) levels were analysed by Western blot and microRNA-1 (miR-1) level was determined by real-time RT-PCR.Key results:Tanshinone IIA decreased the incidence of arrhythmias induced by acute cardiac ischaemia and mortality in rats 3 months after MI. Tanshinone IIA restored the diminished I-K1 current density and Kir2.1 protein after MI in rat ventricular myocytes, while quinidine further inhibited I-K1/Kir2.1. MiR-1 was up-regulated in MI, possibly due to the concomitant increase in SRF, a transcriptional activator of the miR-1 gene, accounting for decreased Kir2.1. Treatment with tanshinone IIA prevented increased SRF and hence increased miR-1 post-MI, whereas quinidine did not.Conclusions and implications:Down-regulation of miR-1 and consequent recovery of Kir2.1 may account partially for the efficacy of tanshinone IIA in suppressing ischaemic arrhythmias and cardiac mortality. These finding support the proposal that miR-1 could be a potential therapeutic target for the prevention of ischaemic arrhythmias.