title: Increased expression of microRNA-146a decreases myocardial ischaemia/reperfusion injury.
abstract: OBJECTIVE
  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-κB) 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-κB activation. This study examined the role of microRNA-146a in myocardial I/R injury.
  
  
  RESULTS
  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-κB activation and inflammatory cytokine production.
  
  
  CONCLUSIONS
  MicroRNA-146a protects the myocardium from I/R injury. The mechanisms may involve attenuation of NF-κB activation and inflammatory cytokine production by suppressing IRAK1 and TRAF6.
authors.affiliation: Department of Surgery,  James H. Quillen College of Medicine, East Tennessee State University, Campus Box 70575, Johnson City, TN 37614-0575,  USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Jianghuan
authors.initials: J
authors.lastname: Zou
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Kalbfleisch
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse