Increased expression of microRNA-146a decreases myocardial ischaemia/reperfusion injury
Increased expression of microRNA-146a decreases myocardial ischaemia/reperfusion injury
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DOI：
10.1093/cvr/cvs356
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发表时间：
2013-03-01
影响因子：
10.8
通讯作者：
Li, Chuanfu
中科院分区：
文献类型：
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作者：
Wang, Xiaohui;Ha, Tuanzhu;Li, Chuanfu
我们已经报道了Toll样受体4缺陷（TLR 4（/））或TLR 2调节对心肌缺血/再灌注（I/R）损伤的保护作用。其机制涉及I/R诱导的核因子KappaB（NF-B）活化的减弱。据报道，microRNA-146 a（miR-146 a）靶向白细胞介素-1受体相关激酶1（IRAK 1）和肿瘤坏死因子（TNF）受体相关因子6（TRAF 6），导致抑制NF-B活化。本研究旨在探讨microRNA-146 a在心肌I/R损伤中的作用。通过右颈总动脉将LmiR-146 a转染到小鼠心脏中。慢病毒载体（LmiR-Con）用作载体对照。未转染的小鼠作为I/R对照。假手术作为假手术对照。转染后7天，使心脏经受缺血（60分钟），随后再灌注（4小时）。氯化三苯基四氮唑（TTC）染色分析心肌梗死面积。在单独的实验中，心脏经受缺血（60分钟），随后再灌注长达7天。在心肌I/R前、I/R后3、7天用超声心动图测定心功能。LmiR-146 a转染显著降低I/R诱导的心肌梗死面积55，并阻止I/R诱导的射血分数（EF）和缩短分数（FS）降低。LmiR-146 a转染减弱I/R诱导的心肌细胞凋亡和caspase-3/7和-8活性。LmiR-146 a转染抑制心肌中IRAK 1和TRAF 6的表达。此外，转染LmiR-146 a可抑制I/R诱导的NF-B活化和炎性细胞因子的产生，保护心肌免受I/R损伤。其机制可能涉及通过抑制IRAK 1和TRAF 6来减弱NF-B活化和炎性细胞因子产生。
We have reported that either toll-like receptor 4 deficiency (TLR4(/)) or TLR2 modulation protects against myocardial ischaemia/reperfusion (I/R) injury. The mechanisms involve attenuation of I/R-induced nuclear factor KappaB (NF-B) activation. MicroRNA-146a (miR-146a) has been reported to target interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), resulting in inhibiting NF-B activation. This study examined the role of microRNA-146a in myocardial I/R injury.We constructed lentivirus expressing miR-146a (LmiR-146a). LmiR-146a was transfected into mouse hearts through the right common carotid artery. The lentivirus vector (LmiR-Con) served as vector control. Untransfected mice served as I/R control. Sham operation served as sham control. Seven days after transfection, the hearts were subjected to ischaemia (60 min) followed by reperfusion (4 h). Myocardial infarct size was analysed by triphenyltetrazolium chloride (TTC) staining. In separate experiments, the hearts were subjected to ischaemia (60 min) followed by reperfusion for up to 7 days. Cardiac function was measured by echocardiography prior to I/R, 3 and 7 days after myocardial I/R. LmiR-146a transfection significantly decreased I/R-induced myocardial infarct size by 55 and prevented I/R-induced decreases in ejection fraction (EF) and fractional shortening (FS). LmiR-146a transfection attenuated I/R-induced myocardial apoptosis and caspase-3/7 and -8 activities. LmiR-146a transfection suppresses IRAK1 and TRAF6 expression in the myocardium. In addition, transfection of LmiR-146a prevented I/R-induced NF-B activation and inflammatory cytokine production.MicroRNA-146a protects the myocardium from I/R injury. The mechanisms may involve attenuation of NF-B activation and inflammatory cytokine production by suppressing IRAK1 and TRAF6.