Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(p...Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(poly(I:C)),a synthetic double-stranded RNA,whether its preconditioning can exhibit a cardioprotective phenotype remains unknown.Here,we report the protective effect of poly(I:C)pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway.Poly(I:C)pretreatment leads to a significant reduction of infarct size,improvement of cardiac function,and downregulation of inflammatory cytokines and apoptotic molecules compared with controls.Subsequently,our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced,and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C)pretreatment,while knock out of TLR3 suppresses the cardioprotection of poly(I:C)preconditioning through a decreased activation of PI3K/Akt signaling.Moreover,inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C)preconditioning-induced cardioprotective effect.In conclusion,our results reveal that poly(I:C)preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3,and the downstream PI3K/Akt signaling,which may provide a potential pharmacologic target for perioperative cardioprotection.展开更多
基金supported by the National Natural Science Foundation of China(Grant nos.81870858 and 81500937 to Dr.Chan ChenNo.81671062 to Dr.Tao Zhu)+1 种基金the National Key R&D Program of China(Grant no.2018YFC2001800 to Dr.Tao Zhu),China Postdoctoral Science Foundation(Grant no.2017M610603 to Dr.Chan Chen)Postdoctoral Science Foundation of Sichuan University(Grant no.2017SCU12030 to Dr.Chan Chen).
文摘Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(poly(I:C)),a synthetic double-stranded RNA,whether its preconditioning can exhibit a cardioprotective phenotype remains unknown.Here,we report the protective effect of poly(I:C)pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway.Poly(I:C)pretreatment leads to a significant reduction of infarct size,improvement of cardiac function,and downregulation of inflammatory cytokines and apoptotic molecules compared with controls.Subsequently,our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced,and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C)pretreatment,while knock out of TLR3 suppresses the cardioprotection of poly(I:C)preconditioning through a decreased activation of PI3K/Akt signaling.Moreover,inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C)preconditioning-induced cardioprotective effect.In conclusion,our results reveal that poly(I:C)preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3,and the downstream PI3K/Akt signaling,which may provide a potential pharmacologic target for perioperative cardioprotection.
