Dexmedetomidine Pretreatment Reduces Myocardial Ischemia-reperfusion Injury Via PERK Pathway In Rats

Objective:This study is aimed to evaluate whether I/R myocardium protection effect from dexmedetomidine preconditioning resulted from the attenuation of excessive endoplasmic reticulum stress and its mediated apoptosis,meanwhile,to investigate the role of PERK pathway in the inhibition of prolong endoplasmic reticulum stress and its mediated apoptosis,and its relationship withα₂-adrenoceptor agonist activation.Methods:Rat hearts were perfused with a Langendorff perfusion system,and randomly assigned to five groups:control group,perfused with K-H solution for 205 min without ischemia.The other four test groups underwent 40 min of global ischemia after the DEX group,YOH group and DEX+YOH group were perfused with DEX（10 nM）,YOH（1μM）or the combination with DEX and YOH,respectively,and followed by 120 min of reperfusion.Cardiac hemodynamics,myocardium infarct size,myocardial histology,myocardial apoptosis rate were evaluated and the expression of glucose-related protein 78（GRP78）,Protein kinase R-like ER kinase（PERK）,p-PERK,eukaryotic initiation factor 2a（eIF2a）,p-eIF2a,activating transcription factor 4（ATF4）,CCAAT/enhancer-binding protein homologous protein（CHOP）were assessed by Western blotting.Results:⑴There was no difference in cardiac hemodynamics between the groups at T₁（P（29）0.05）.At the time of T₂,there were no significant between-group differences for HR,±dp/dt_max,LVDP,LVEDP,and RPP without YOH group and DEX+YOH group.Compared with T₁,the HR and LVEDP were increased,±dp/dt_max,LVDP and RPP of T₃were decreased in Control group（P<0.05）;the HR,±dp/dt_max,LVDP and RPP of T₃ in other four groups were significantly decreased,and LVEDP was significantly increased（P<0.05）.At the time of T₃,compared with the Control group,the HR,±dp/dt_max,LVDP,and RPP of the other groups decreased significantly,and LVEDP increased significantly（P<0.05）.Compared with DEX group,the HR,±dp/dtmax,LVDP and RPP in the YOH group and DEX+YOH group were significantly decreased,and the LVEDP was significantly increased（P<0.05）.Compared with the I/R group,the HR and±dp/dt_max,LVDP,RPP were significantly increased,LVEDP were significantly decreased in DEX group（P<0.05）,but there was no significant difference in cardiac function between YOH group and DEX+YOH group（P（29）0.05）.⑵Compared with the Control group,the myocardial infarct size and myocardial apoptosis rate of the other groups were significantly increased（P<0.05）.Compared with DEX group,myocardial infarct size and the apoptotic rate of cardiomyocytes increased significantly in YOH group and DEX+YOH group（P<0.05）.Compared with the I/R group,the myocardial infarct size and myocardial apoptosis rate in the DEX group were significantly reduced（P<0.05）,there was no significant difference between YOH group and DEX+YOH group（P（29）0.05）.There was no significant difference in myocardial infarct size and cardiomyocyte apoptosis rate between the DEX+YOH group and the YOH group（P（29）0.05）.⑶Under light microscope:myocardial structure is complete and regular arrangement,normal cardiac muscle fibers,with mild cardiomyocyte edema in control group,while the normal structure of the myocardium was severely damaged after undergoing ischemia-reperfusion injury.The main manifestations in I/R group,YOH group and DEX+YOH group are disordered myofibril arrangement and ruptured cardiac muscle fibers.On the contrary,in the DEX group,the normal myocardial structure was less damaged,and the myocardial fiber structure was continuously ordered and mild myocardial cell edema.⑷Compared with the control group,GRP78,p-PERK,p-eIF2a,ATF4 and CHOP protein were increased in I/R group,YOH group and DEX+YOH group（P<0.05）,while the expression of these protein in DEX group were increased,the difference was not statistically significant（P（29）0.05）;compared with I/R group,GRP78,p-PERK,p-eIF2a,ATF4 and CHOP protein were significantly reduced in DEX group（P<0.05）,GRP78protein and CHOP protein expression levels were significantly decreased in YOH group（P<0.05）,the expression of PERK protein and CHOP protein expression levels were significantly decreased in DEX+YOH group（P<0.05）.Compared with DEX group,GRP78,p-PERK,p-eIF2a,ATF4 and CHOP protein were increased in YOH group and DEX+YOH group（P<0.05）;there was no significant difference in DEX+YOH group and YOH group（P（29）0.05）.Conclusion:（1）Dexmedetomidine preconditioning may protect myocardial ischemia-reperfusion injury by inhibiting excessive endoplasmic reticulum stress and apoptosis mediated by PERK pathway.（2）The inhibition of PERK pathway may be related to dexmedetomidine activatinga₂ adrenergic receptor.