PI3K/Akt信号通路在肝脏缺血再灌注损伤中的研究进展
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摘要
肝脏缺血再灌注损伤是导致术后肝脏功能延迟恢复和功能障碍的重要原因。有研究表明,PI3K/Akt信号通路在缺血和再灌注的过程中被激活,通过抑制或增强下游相关靶蛋白的表达发挥对肝脏的保护作用。因此,PI3K/Akt信号成为预防和改善肝脏缺血再灌注损伤的重要靶向通路。本文就PI3K/Akt信号通路在肝脏缺血再灌注损伤中作用的研究进展进行综述。
Liver ischemia-reperfusion injury is the leading cause of delayed recovery of liver function and dysfunction after operation.Some studies have shown that PI3K/Akt signaling pathway is activated during ischemia and reperfusion,which plays a protective role on the liver by inhibiting or enhancing the expressions of downstream target proteins.Therefore,PI3K/Akt signaling has become an important target pathway for preventing and improving hepatic ischemia-reperfusion injury.This review summarized the research progresses of PI3K/Akt signaling pathway in hepatic ischemia-reperfusion injury.
Liver ischemia-reperfusion injury is the leading cause of delayed recovery of liver function and dysfunction after operation.Some studies have shown that PI3K/Akt signaling pathway is activated during ischemia and reperfusion,which plays a protective role on the liver by inhibiting or enhancing the expressions of downstream target proteins.Therefore,PI3K/Akt signaling has become an important target pathway for preventing and improving hepatic ischemia-reperfusion injury.This review summarized the research progresses of PI3K/Akt signaling pathway in hepatic ischemia-reperfusion injury.
引文
[1]EGGENHOFER E,SABET-RASHEDI M,LANTOW M,et al.RORγt(+)IL-22-producing NKp46(+)cells protect from hepatic ischemia reperfusion injury in mice[J].J Hepatol,2015,64(1):128-134.
[2]PERALTA C,JIMENEZ-CASTRO M B,GRACIASANCHO J.Hepatic ischemia and reperfusion injury:effects on the liver sinusoidal milieu[J].J Hepatol,2013,59(5):1094-1106.
[3]毛长坤,刘付宝,耿小平.P38MAPK信号转导通路及其与缺血再灌注损伤的关系[J].肝胆外科杂志,2013,21(6):477-478.
[4]于恒超.Notch信号通路在肝脏缺血再灌注损伤中的作用及作用机制[D].第四军医大学学位论文,2011.
[5]吴鹏俐,钟坪杉,阳德飞,等.肝缺血再灌注损伤分子机制的研究进展[J].局解手术学杂志,2017,26(6):10-15.
[6]富智,黄苏,莫绪明,等.NF-κB在大鼠肝缺血再灌注损伤与缺血预处理保护机制中的作用[J].中华临床医师杂志(电子版),2013,7(13):5961-5965.
[7]KIM H J,JOE Y,KONG J S,et al.Carbon Monoxide protects against hepatic ischemia/reperfusion injury via ROSDependent Akt signaling and inhibition of glycogen synthase kinase 3β[J].Oxid Med Cell Longev,2013,2013:306421.
[8]JIA J,LI J,JIANG L,et al.Protective effect of remote limb ischemic perconditioning on the liver grafts of rats with a novel model[J].Plos One,2015,10(3):e0121972.
[9]HE N,JIA J J,LI J H,et al.Remote ischemic perconditioning prevents liver transplantation-induced ischemia/reperfusion injury in rats:role of ROS/RNS and Enos[J].World J Gastroenterol,2017,23(5):830-841.
[10]HARADA N,HATANO E,KOIZUMI N,et al.Akt activation protects rat liver from ischemia/reperfusion injury[J].J Surq Res,2004,121(2):159-170.
[11]ZHANG R,ZHANG L,MANAENKO A,et al.Helium preconditioning protects mouse liver against ischemia and reperfusion injury through the PI3K/Akt pathway[J].J Hepatol,2014,61(5):1048-1055.
[12]ZHAI Y,BUSUTTIL R W,KUPIECWEGLINSKI J W.Liver ischemia and reperfusion injury:new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation[J].Am J Transplant,2011,11(8):1563-1569.
[13]索立达,佟立权.PI3K-Akt信号传导通路在缺血再灌注损伤中的研究进展[J].河北医科大学学报,2014,35(2):237-240.
[14]DATTA S R,BRUNET A,GREENBERG M E.Cellular survival:aplay in three Akts[J].Genes Dev,1999,13(22):2905-2927.
[15]LIU T,ZHANG Q,MO W,et al.The protective effeces of shikonin on hepatic ischemia/reperfusion injury by the activation of the PI3K/Akt pathway[J].Sci Rep,2017,7:44785.
[16]CALDWELL-KENKEL J C,CURRIN R T,TANAKA Y,et al.Reperfusion injury to endothelial cells following cold ischemic storage of rat livers[J].Hepatology,1989,10(3):292-299.
[17]IKEDA T,YANAQA K,KISHIKAWA K,et al.Ischemic injury in liver transplantation:difference in injury sites between warm and cold ischemia in rats[J].Hepatology,1992,16(2):454-461.
[18]LI X,WU Y,ZHANG W,et al.Pre-conditioning with tanshinoneⅡA attenuates the ischemia/reperfusion injury caused by liver grafts via regulation of HMGB1in rat Kupffer cells[J].Biomed pharmacother,2017,89:1392-1400.
[19]MIYAMOTO H,DOITA M,NISHIDA K,et al.Effects of cyclic mechanical stress on the production of inflammatory agents by nucleus pulposus and anulus fibrosus derived cells in vitro[J].Spine(Phila Pa 1976),2006,31(1):4-9.
[20]YU H C,QIN H Y,HE F,et al.Canonical notch pathway protects hepatocytes from ischemia/reperfusion injury in mice by repressing reactive oxygen species production through JAK2/STAT3signaling[J].Hepatology,2011,54(3):979-988.
[21]KIM J S,WANG J H,LEMASTERS J J.Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation:role of Ca2+-dependent mitochondrial formation of reactive oxygen species[J].Am J Physiol Gastrointest Liver Physiol,2012,302(7):G723-G731.
[22]NDIAYE M,CHATAIQNEAU M,LOBYSHENAL L,et al.Red wine polyphenol-induced endothelium-dependent NOmediated relaxation is due to the PI3kinase/Akt-dependent phosphorylation of endothelial NO synthase in the isolated porcine coronary artery[J].FASEB J,2005,19(3):455-457.
[23]DATTA S R,DUDEK H,TAO X,et al.Akt phosphorylation of BAD couples survival signals to the cellintrinsic death machinery[J].Cell,1997,91(2):231-241.
[24]DATTA S R,BRUNET A,GREENBERG M E.Cellular survival:aplay in three Akts[J].Genes Dev,1999,13(22):2905-2927.
[25]JALOWY A,SCHULZ R,HEUSCH G.AT1 receptor blockade in experimental myocardial ischemia/reperfusion[J].Basic Res Cardiol,1998,93Suppl 2:85-91.
[26]KUBOTA I,HAN X,OPEL D J,et al.Increased susceptibility to development of triggered activity in myocytes from mice with targeted disruption of endothelial nitric oxide synthase[J].J Mol Cell Cardiol,2000,32(7):1239-1248.
[27]FU W,LIAO X,RUAN J,et al.Recombinant human erythropoietin preconditioning attenuates liver ischemia reperfusion injury through the phosphatidylinositol-3kinase/AKT/endothelial nitric oxide synthase pathway[J].J Surg,2013,183(2):876-884.
[28]GUI B,HUA F,CHENJ,et al.Protective effects of pretreatment with oleanolic acid in rats in the acute phase of hepatic ischemia-reperfusion injury:role of the PI3K/Akt pathway[J].Mediators Inflamm,2014,2014:451826.
[29]SHENG M,ZHOU Y,YU W,et al.Protective effect of Berberine pretreatment in hepatic ischemia/reperfusion injury of rat[J].Transplant Proc,2015,47(2):275-282.
[30]KOH P O.Melatonin prevents hepatic injury-induced decrease in Akt downstream targets phosphorylations[J].J Pineal Res,2011,51(2):214-219.
[31]王菲,贾莉莉,翁亦齐,等.线粒体自噬在缺血再灌注损伤中作用的研究进展[J].中华器官移植杂志,2015,36(8):503-505.
[32]王超臣,张培建.线粒体自噬在肝相关疾病中的作用[J].中华普通外科学文献(电子版),2013,7(5):55-57.
[33]ZOROV D B,JUHASZOVA M,SOLLOTT S J.Mitochondrial reactive oxygen species(ROS)and ROSinduced ROS release[J].Physio Rev,2014,94(3):909-950.
[34]MATHEW R,KARANTZA-WADSWORTH V,WHITE E.Role of autophagy in cancer[J].Nat Rev Cancer,2007,7(12):961-967.
[35]RAUTOU P E,MANSOURI A,LEBREC D,et al.Autophagy in liver diseases[J].J Hepatol,2010,53(6):1123-1134.
[36]WANG D,MA Y,LI Z,et al.The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice[J].Autophagy,2012,8(6):954-962.
[37]CZAJA M J,DING W X,DONOHUE T M JR,et al.Functions of autophagy in normal and diseased liver[J].Autophagy,2013,9(8):1131-1158.
[38]WANG J H,AHN I S,FISCHER T D,et al.Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice[J].Gastroenterology,2011,141(6):2188-2199.
[39]徐玉彬,张培建,毛旭南,等.凋亡和自噬在肝脏缺血再灌注损伤中的作用[J].中华医学杂志,2016,96(28):2274-2276.
[40]YANG J,CHEN Q,TIAN S,et al.The role of 1,25-dyhydroxyvitamin D3in mouse liver ischemia reperfusion injury:regulation of autophagy through activation of MEK/ERK signaling and PTEN/PI3K/Akt/mTORC1 signaling[J].Am J Transl Res,2015,7(12):2630-2645.
[41]ZHONG C,PU L Y,FANG M M,et al.Retinoic acid receptorαpromotes autophagy to alleviate liver ischemia and reperfusion injury[J].World J Gastroentero,2015,21(43):12381-12391.
[2]PERALTA C,JIMENEZ-CASTRO M B,GRACIASANCHO J.Hepatic ischemia and reperfusion injury:effects on the liver sinusoidal milieu[J].J Hepatol,2013,59(5):1094-1106.
[3]毛长坤,刘付宝,耿小平.P38MAPK信号转导通路及其与缺血再灌注损伤的关系[J].肝胆外科杂志,2013,21(6):477-478.
[4]于恒超.Notch信号通路在肝脏缺血再灌注损伤中的作用及作用机制[D].第四军医大学学位论文,2011.
[5]吴鹏俐,钟坪杉,阳德飞,等.肝缺血再灌注损伤分子机制的研究进展[J].局解手术学杂志,2017,26(6):10-15.
[6]富智,黄苏,莫绪明,等.NF-κB在大鼠肝缺血再灌注损伤与缺血预处理保护机制中的作用[J].中华临床医师杂志(电子版),2013,7(13):5961-5965.
[7]KIM H J,JOE Y,KONG J S,et al.Carbon Monoxide protects against hepatic ischemia/reperfusion injury via ROSDependent Akt signaling and inhibition of glycogen synthase kinase 3β[J].Oxid Med Cell Longev,2013,2013:306421.
[8]JIA J,LI J,JIANG L,et al.Protective effect of remote limb ischemic perconditioning on the liver grafts of rats with a novel model[J].Plos One,2015,10(3):e0121972.
[9]HE N,JIA J J,LI J H,et al.Remote ischemic perconditioning prevents liver transplantation-induced ischemia/reperfusion injury in rats:role of ROS/RNS and Enos[J].World J Gastroenterol,2017,23(5):830-841.
[10]HARADA N,HATANO E,KOIZUMI N,et al.Akt activation protects rat liver from ischemia/reperfusion injury[J].J Surq Res,2004,121(2):159-170.
[11]ZHANG R,ZHANG L,MANAENKO A,et al.Helium preconditioning protects mouse liver against ischemia and reperfusion injury through the PI3K/Akt pathway[J].J Hepatol,2014,61(5):1048-1055.
[12]ZHAI Y,BUSUTTIL R W,KUPIECWEGLINSKI J W.Liver ischemia and reperfusion injury:new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation[J].Am J Transplant,2011,11(8):1563-1569.
[13]索立达,佟立权.PI3K-Akt信号传导通路在缺血再灌注损伤中的研究进展[J].河北医科大学学报,2014,35(2):237-240.
[14]DATTA S R,BRUNET A,GREENBERG M E.Cellular survival:aplay in three Akts[J].Genes Dev,1999,13(22):2905-2927.
[15]LIU T,ZHANG Q,MO W,et al.The protective effeces of shikonin on hepatic ischemia/reperfusion injury by the activation of the PI3K/Akt pathway[J].Sci Rep,2017,7:44785.
[16]CALDWELL-KENKEL J C,CURRIN R T,TANAKA Y,et al.Reperfusion injury to endothelial cells following cold ischemic storage of rat livers[J].Hepatology,1989,10(3):292-299.
[17]IKEDA T,YANAQA K,KISHIKAWA K,et al.Ischemic injury in liver transplantation:difference in injury sites between warm and cold ischemia in rats[J].Hepatology,1992,16(2):454-461.
[18]LI X,WU Y,ZHANG W,et al.Pre-conditioning with tanshinoneⅡA attenuates the ischemia/reperfusion injury caused by liver grafts via regulation of HMGB1in rat Kupffer cells[J].Biomed pharmacother,2017,89:1392-1400.
[19]MIYAMOTO H,DOITA M,NISHIDA K,et al.Effects of cyclic mechanical stress on the production of inflammatory agents by nucleus pulposus and anulus fibrosus derived cells in vitro[J].Spine(Phila Pa 1976),2006,31(1):4-9.
[20]YU H C,QIN H Y,HE F,et al.Canonical notch pathway protects hepatocytes from ischemia/reperfusion injury in mice by repressing reactive oxygen species production through JAK2/STAT3signaling[J].Hepatology,2011,54(3):979-988.
[21]KIM J S,WANG J H,LEMASTERS J J.Mitochondrial permeability transition in rat hepatocytes after anoxia/reoxygenation:role of Ca2+-dependent mitochondrial formation of reactive oxygen species[J].Am J Physiol Gastrointest Liver Physiol,2012,302(7):G723-G731.
[22]NDIAYE M,CHATAIQNEAU M,LOBYSHENAL L,et al.Red wine polyphenol-induced endothelium-dependent NOmediated relaxation is due to the PI3kinase/Akt-dependent phosphorylation of endothelial NO synthase in the isolated porcine coronary artery[J].FASEB J,2005,19(3):455-457.
[23]DATTA S R,DUDEK H,TAO X,et al.Akt phosphorylation of BAD couples survival signals to the cellintrinsic death machinery[J].Cell,1997,91(2):231-241.
[24]DATTA S R,BRUNET A,GREENBERG M E.Cellular survival:aplay in three Akts[J].Genes Dev,1999,13(22):2905-2927.
[25]JALOWY A,SCHULZ R,HEUSCH G.AT1 receptor blockade in experimental myocardial ischemia/reperfusion[J].Basic Res Cardiol,1998,93Suppl 2:85-91.
[26]KUBOTA I,HAN X,OPEL D J,et al.Increased susceptibility to development of triggered activity in myocytes from mice with targeted disruption of endothelial nitric oxide synthase[J].J Mol Cell Cardiol,2000,32(7):1239-1248.
[27]FU W,LIAO X,RUAN J,et al.Recombinant human erythropoietin preconditioning attenuates liver ischemia reperfusion injury through the phosphatidylinositol-3kinase/AKT/endothelial nitric oxide synthase pathway[J].J Surg,2013,183(2):876-884.
[28]GUI B,HUA F,CHENJ,et al.Protective effects of pretreatment with oleanolic acid in rats in the acute phase of hepatic ischemia-reperfusion injury:role of the PI3K/Akt pathway[J].Mediators Inflamm,2014,2014:451826.
[29]SHENG M,ZHOU Y,YU W,et al.Protective effect of Berberine pretreatment in hepatic ischemia/reperfusion injury of rat[J].Transplant Proc,2015,47(2):275-282.
[30]KOH P O.Melatonin prevents hepatic injury-induced decrease in Akt downstream targets phosphorylations[J].J Pineal Res,2011,51(2):214-219.
[31]王菲,贾莉莉,翁亦齐,等.线粒体自噬在缺血再灌注损伤中作用的研究进展[J].中华器官移植杂志,2015,36(8):503-505.
[32]王超臣,张培建.线粒体自噬在肝相关疾病中的作用[J].中华普通外科学文献(电子版),2013,7(5):55-57.
[33]ZOROV D B,JUHASZOVA M,SOLLOTT S J.Mitochondrial reactive oxygen species(ROS)and ROSinduced ROS release[J].Physio Rev,2014,94(3):909-950.
[34]MATHEW R,KARANTZA-WADSWORTH V,WHITE E.Role of autophagy in cancer[J].Nat Rev Cancer,2007,7(12):961-967.
[35]RAUTOU P E,MANSOURI A,LEBREC D,et al.Autophagy in liver diseases[J].J Hepatol,2010,53(6):1123-1134.
[36]WANG D,MA Y,LI Z,et al.The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice[J].Autophagy,2012,8(6):954-962.
[37]CZAJA M J,DING W X,DONOHUE T M JR,et al.Functions of autophagy in normal and diseased liver[J].Autophagy,2013,9(8):1131-1158.
[38]WANG J H,AHN I S,FISCHER T D,et al.Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice[J].Gastroenterology,2011,141(6):2188-2199.
[39]徐玉彬,张培建,毛旭南,等.凋亡和自噬在肝脏缺血再灌注损伤中的作用[J].中华医学杂志,2016,96(28):2274-2276.
[40]YANG J,CHEN Q,TIAN S,et al.The role of 1,25-dyhydroxyvitamin D3in mouse liver ischemia reperfusion injury:regulation of autophagy through activation of MEK/ERK signaling and PTEN/PI3K/Akt/mTORC1 signaling[J].Am J Transl Res,2015,7(12):2630-2645.
[41]ZHONG C,PU L Y,FANG M M,et al.Retinoic acid receptorαpromotes autophagy to alleviate liver ischemia and reperfusion injury[J].World J Gastroentero,2015,21(43):12381-12391.