Mechanism of Mitochondrial Autophagy Mediated by BDNF/TrkB Signaling Pathway on Myocardial Ischemia-reperfusion Injury
Objective:To explore the mechanism of mitochondrial autophagy mediated by brain-derived neurotrophic factor(BDNF)/tropomyosin receptor kinase B(TrkB)signaling pathway on myocardial ischemia-reperfusion(I/R)injury.Methods:The mice were randomly divided into Sham+phosphate buffer(PBS)group,Sham+7,8-dihydroxyflavone(7,8-DHF)group,I/R+PBS group and I/R+7,8-DHF group,with 12 mice in each group.Myocardial I/R injury model(myocardial ischemia 45 min/reperfusion 2 h)were established in other mice except Sham group.Mice in Sham+7,8-DHF group and I/R+7,8-DHF group were intraperitoneally injected with 7,8-DHF 7 d before myocardial I/R injury.Sham+PBS group and I/R+PBS group were given the same volume of PBS.Echocardiography,hematoxylin-eosin(HE)staining and immunohistochemistry were used to detect cardiac function,histology,and intercellular adhesion molecule-1(ICAM-1)expression.Cardiac microvascular endothelial cells(CMEC)were isolated from the hearts of mice in each group.TrkB small interfering RNA(si-TrkB)was transfected into CMEC cells to inhibit TrkB activation,and then the opening rate of mitochondrial membrane permeability transition pore(mPTP)was measured.Results:In the I/R+PBS group,red blood cells clustered after I/R injury,while in the I/R+7,8-DHF group,the linear morphology of red blood cells were maintained and the convergence in microvessels was prevented.Compared with I/R+PBS group,P-ENOS level,ventricular septal thickness,left ventricular short axis shortening fraction,and left ventricular ejection fraction in I/R+7,8-DHF group increased(P<0.05).Endothelin-1(ET-1),ICAM-1,heart mass,heart mass index,left ventricular end-diastolic diameter and left ventricular end-systolic diameter were down regulated(P<0.05).The expression of BDNF,TrkB,FUN14 domain 1(FUNDC1)protein and the formation of acid autolyssome in CMEC in I/R+PBS group decreased compared with those in Sham+PBS group(P<0.05),the expression of BDNF,TrkB,FUNDC1 protein and the formation of acid autolyssome in CMEC in I/R+7,8-DHF group increased compared with those in I/R+PBS group(P<0.05).When si-TrkB was administered in the presence of 7,8-DHF to inhibit TrkB activation in CMEC,FUNDC1 expression was inhibited(P<0.05),and mitochondrial levels of mito-LC3Ⅱand acid autolyssome formation were reduced(P<0.05).Conclusion:Activation of the BDNF/TrkB/FUNDC1 signaling pathway improved endothelial function and microvascular structure in I/R mice by restoring mitochondrial autophagy.
myocardial ischemia-reperfusionmitochondrial autophagybrain-derived neurotrophic factortropomyosin receptor kinase B7,8-dihydroxyflavoneexperimental study
NETL
NSTL
万方数据
