苦参提取物通过JAK/STAT信号通路减轻缺血再灌注大鼠心肌损伤的实验研究
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摘要
目的探讨苦参提取物减轻缺血再灌注大鼠心肌损伤的机制。方法建立大鼠缺血再灌注心肌损伤模型,给予氧化苦参碱处理,观察处理后心肌氧化应激指标变化、心肌细胞凋亡情况及JAK/STAT信号通路关键分子变化。结果缺血再灌注组p-JAK2、p-STAT1、p-STAT3表达量显著高于假手术组(P<0.05)。氧化苦参碱组p-JAK2、p-STAT1、p-STAT3表达量显著低于缺血再灌注组(P<0.05)。缺血再灌注组细胞凋亡指数显著高于假手术组(P<0.01)。给予氧化苦参碱处理后,细胞凋亡指数显著低于缺血再灌注组(P<0.05)。缺血再灌注组心肌NO、SOD、GSH-PX含量显著低于假手术组,MDA含量显著高于假手术组(P<0.05)。氧化苦参碱组NO、SOD、GSH-PX含量显著高于缺血再灌注组,MDA含量显著低于缺血再灌注组(P<0.05)。给予JAK抑制剂AG490+氧化苦参碱处理后p-JAK2、p-STAT1、p-STAT3含量显著低于仅给予JAK抑制剂组。给予STAT抑制剂西罗莫司(sirolimus)+氧化苦参碱处理后,p-JAK2、p-STAT1、pSTAT3含量显著低于仅给予STAT抑制剂sirolimus处理组(P<0.05)。结论苦参提取物可通过抑制JAK/STAT信号通路,减轻缺血再灌注大鼠心肌氧化损伤。
Objective To investigate the specific mechanism of matrine extraction in alleviating myocardial injury in rats with ischemiareperfusion.Methods The model of myocardial ischemiavreperfusion injury in rats was established and treated with oxymatrine.The changes of oxidative stress index,apoptosis of myocardial cells and the changes of key molecules in JAK/STAT signaling pathway were observed.Results The expression levels of p-JAK2,p-STAT1 and p-STAT3 in ischemiareperfusion group weresignificantly higher than those in sham operation group(P<0.05).The expression levels of p-JAK2,p-STAT1 and p-STAT3 in oxymatrine group were significantly lower than those in ischemiareperfusion group(P<0.05).The apoptosis index in ischemia reperfusion group was significantly higher than that in sham operation group(P<0.01).After treatment with oxymatrine,the apoptosis index was significantly lower than that in ischemiareperfusion group(P<0.05).The contents of NO,SOD and GSH-PX in ischemiareperfusion group were significantly lower than those in sham operation group while the MDA content was significantly higher than that in sham operation group(P<0.05).The contents of NO,SOD and GSH-PX in oxymatrine group were significantly higher than those in ischemiareperfusion group while the MDA content was significantly lower than that in ischemiareperfusion group(P<0.05).The content of p-JAK2,p-STAT1,and p-STAT3 after treatment with JAK inhibitor AG490+ oxymatrine was significantly lower than that of the JAK inhibitor alone group.After treatment with the STAT inhibitor sirolimus+ oxymatrine,the levels of p-JAK2,p-STAT1,and p-STAT3 were significantly lower than those treated with the STAT inhibitor sirolimus alone(P<0.05).Conclusion Matrine extraction can alleviate myocardial oxidative injury in rats with ischemiareperfusion by inhibiting JAK/STAT signaling pathway.
Objective To investigate the specific mechanism of matrine extraction in alleviating myocardial injury in rats with ischemiareperfusion.Methods The model of myocardial ischemiavreperfusion injury in rats was established and treated with oxymatrine.The changes of oxidative stress index,apoptosis of myocardial cells and the changes of key molecules in JAK/STAT signaling pathway were observed.Results The expression levels of p-JAK2,p-STAT1 and p-STAT3 in ischemiareperfusion group weresignificantly higher than those in sham operation group(P<0.05).The expression levels of p-JAK2,p-STAT1 and p-STAT3 in oxymatrine group were significantly lower than those in ischemiareperfusion group(P<0.05).The apoptosis index in ischemia reperfusion group was significantly higher than that in sham operation group(P<0.01).After treatment with oxymatrine,the apoptosis index was significantly lower than that in ischemiareperfusion group(P<0.05).The contents of NO,SOD and GSH-PX in ischemiareperfusion group were significantly lower than those in sham operation group while the MDA content was significantly higher than that in sham operation group(P<0.05).The contents of NO,SOD and GSH-PX in oxymatrine group were significantly higher than those in ischemiareperfusion group while the MDA content was significantly lower than that in ischemiareperfusion group(P<0.05).The content of p-JAK2,p-STAT1,and p-STAT3 after treatment with JAK inhibitor AG490+ oxymatrine was significantly lower than that of the JAK inhibitor alone group.After treatment with the STAT inhibitor sirolimus+ oxymatrine,the levels of p-JAK2,p-STAT1,and p-STAT3 were significantly lower than those treated with the STAT inhibitor sirolimus alone(P<0.05).Conclusion Matrine extraction can alleviate myocardial oxidative injury in rats with ischemiareperfusion by inhibiting JAK/STAT signaling pathway.
引文
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[16]Boengler K,Hilfiker-Kleiner D,Drexler H,et al.The myocardial JAK/STAT pathway:from protection to failure[J].Pharmacol Ther,2008,120(2):172-185
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[19]Rafiee P,Shi Y,Su J,et al.Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways[J].Basic Res Cardiol,2005,100(3):187-197
[20]Freed D H,Borowiec A M,Angelovska T,et al.Induction of protein synthesis in cardiac fibroblasts by cardiotrophin-1:integration of multiple signaling pathways[J].Cardiovasc Res,2003,60(2):365-375
[2]Erkasap S,Erkasap N,Bradford B,et al.The effect of leptin and resveratrol on JAK/STAT pathways and Sirt-1 gene expression in the renal tissue of ischemia/reperfusion induced rats[J].Bratisl Lek Listy,2017,118(8):443-448
[3]Barsukevich V,Basalay M,Sanchez J,et al.Distinct cardioprotective mechanisms of immediate,early and delayed ischaemic postconditioning[J].Basic Res Cardiol,2015,110(1):452
[4]Bibli S I,Iliodromitis E K,Lambertucci C,et al.Pharmacological postconditioning of the rabbit heart with non-selective,A1,A2A and A3 adenosine receptor agonists[J].J Pharm Pharmacol,2014,66(8):1140-1149
[5]Susnik N,Sorensen-Zender I,Rong S,et al.Ablation of proximal tubular suppressor of cytokine signaling3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury[J].Kidney Int,2014,85(6):1357-1368
[6]Macchi L,Moussa W B,Guillou S,et al.The synthetic pentasaccharide fondaparinux attenuates myocardial ischemia-reperfusion injury in rats via STAT-3[J].Shock,2014,41(2):166-171
[7]Lemoine S,Zhu L,Legallois D,et al.Atorvastatininduced cardioprotection of human myocardium is mediated by the inhibition of mitochondrial permeability transition pore opening via tumor necrosis factor-alpha and Janus kinase/signal transducers and activators of transcription pathway[J].Anesthesiology,2013,118(6):1373-1384
[8]Fahmi A,Smart N,Punn A,et al.p42/p44-MAPKand PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation[J].Cell Signal,2013,25(4):898-909
[9]Correa-Costa M,Azevedo H,Amano M T,et al.Transcriptome analysis of renal ischemia/reperfusion injury and its modulation by ischemic pre-conditioning or hemin treatment[J].PLoS One,2012,7(11):49569
[10]Wen S H,Li Y,Li C,et al.Ischemic postconditioning during reperfusion attenuates intestinal injury and mucosal cell apoptosis by inhibiting JAK/STAT signaling activation[J].Shock,2012,38(4):411-419
[11]Smith C C,Dixon R A,Wynne A M,et al.Leptininduced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore[J].Am J Physiol Heart Circ Physiol,2010,299(4):1265-1270
[12]Freitas M C,Uchida Y,Zhao D,et al.Blockade of Janus kinase-2 signaling ameliorates mouse liver damage due to ischemia and reperfusion[J].Liver Transpl,2010,16(5):600-610
[13]Wagner M,Siddiqui M A.Signaling networks regulating cardiac myocyte survival and death[J].Curr Opin Investig Drugs,2009,10(9):928-937
[14]Li Q,Zhang R,Guo Y L,et al.Effect of neuregulin on apoptosis and expressions of STAT3 and GFAP in rats following cerebral ischemic reperfusion[J].J Mol Neurosci,2009,37(1):67-73
[15]Yang N,Luo M,Li R,et al.Blockage of JAK/STATsignalling attenuates renal ischaemia-reperfusion injury in rat[J].Nephrol Dial Transplant,2008,23(1):91-100
[16]Boengler K,Hilfiker-Kleiner D,Drexler H,et al.The myocardial JAK/STAT pathway:from protection to failure[J].Pharmacol Ther,2008,120(2):172-185
[17]An W,Yang J,Ao Y.Metallothionein mediates cardioprotection of isoliquiritigenin against ischemiareperfusion through JAK2/STAT3 activation[J].Acta Pharmacol Sin,2006,27(11):1431-1437
[18]Gross E R,Hsu A K,Gross G J.The JAK/STATpathway is essential for opioid-induced cardioprotection:JAK2 as a mediator of STAT3,Akt,and GSK-3beta[J].Am J Physiol Heart Circ Physiol,2006,291(2):827-834
[19]Rafiee P,Shi Y,Su J,et al.Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways[J].Basic Res Cardiol,2005,100(3):187-197
[20]Freed D H,Borowiec A M,Angelovska T,et al.Induction of protein synthesis in cardiac fibroblasts by cardiotrophin-1:integration of multiple signaling pathways[J].Cardiovasc Res,2003,60(2):365-375