腺苷酸活化蛋白激酶与缺血再灌注损伤的研究进展-现代医学

腺苷酸活化蛋白激酶与缺血再灌注损伤的研究进展

单位：1. 遵义医科大学研究生院, 贵州遵义 563000;
2. 贵州省人民医院肝胆外科, 贵州贵阳 550000;
3. 贵州省人民医院急诊外科, 贵州贵阳 550000

分类号：R363

出版年·卷·期（页码）：2020·48·第一期（141-145）

摘要：

腺苷酸活化蛋白激酶（AMP-activated kinase， AMPK）存在于真核生物各组织、细胞中，是一种突变率低且相对保守的丝氨酸-苏氨酸激酶，是生物体内一种重要的信号通路，是维持生物能量稳定、平衡的重要调节器，被称为"能量调控枢纽站"。目前研究显示：AMPK信号通路在能量代谢、糖代谢、脂肪代谢、蛋白质代谢中发挥着重要的作用，但其具体的病理生理过程及确切的机制尚未明确。近年来发现，AMPK与衰老、肥胖、心血管病、肿瘤等疾病有着密切的关系，尤其在心^[1]、脑^[2]、肾^[3]、肝^[4]等重要器官的缺血再灌注损伤（ischemia-reperfusion injury，IRI）中备受研究。有研究表明^[5]：当机体发生缺血再灌注损伤而引起组织、细胞能量供给不足及代谢紊乱等改变时，AMPK将作为一种重要的保护机制系统而被激活，保证机体内环境维持在一个动态平衡状态。因此，以AMPK信号通路为中心作为重要器官IRI的治疗靶点，将会是一个突破性的研究。

Objective: Adenosine-activated protein kinase exists in various tissues and cells of eukaryotic organisms. It is a relatively conservative serine-threonine kinase with low mutation rate. It is an important signaling pathway in organisms and an important regulator to maintain the stability and balance of biological energy. It is called "energy control hub". Current studies have shown that AMPK signaling pathway plays an important role in energy metabolism, sugar metabolism, fat metabolism and protein metabolism, but its specific pathophysiological process and exact mechanism are not yet clear. In recent years, AMPK has been found to be closely related to aging, obesity, cardiovascular diseases, tumors and other diseases, especially in the ischemia-reperfusion injury of important organs such as heart^[1], brain^[2], kidney^[3], liver^[4]. Studies have shown that^[5] AMPK will be activated as an important protective mechanism system when ischemia-reperfusion injury causes changes in tissue, cell energy supply deficiency and metabolic disorders, so as to ensure that the internal environment of the body maintains a dynamic balance. Therefore, taking AMPK signaling pathway as the treatment target of IRI in important organs will be a breakthrough research.

参考文献：

[1] HUANG L,DAI K,CHEN M,et al.The AMPK agonist PT1 and mTOR inhibitor 3HOI-BA-01 protect cardiomyocytes after ischemia through induction of autophagy[J].Journal of Cardiovascular Pharmacology and Therapeutics,2016,21(1):70-81.
[2] LI L,XIAO L,HOU Y,et al.Sestrin2 silencing exacerbates cerebral ischemia/reperfusion injury by decreasing mitochondrial biogenesis through the AMPK/PGC-1α pathway in rats[J].Scientific Reports,2016,6(1):30272-30272.
[3] 周俊,林文静,林森,et al.AMPK通过抑制炎性反应减轻小鼠肾脏缺血再灌注后纤维化[J].中华肾脏病杂志,2016,32(6):450-456.
[4] JIMENEZCASTRO M B,CASILLASRAMIREZ A,MENDESBRAZ M,et al.Adiponectin and resistin protect steatotic livers undergoing transplantation[J].Journal of Hepatology,2013,59(6):1208-1214.
[5] XIA M,DING Q,ZHANG Z,et al.Remote limb ischemic preconditioning protects rats against cerebral ischemia via HIF-1α/AMPK/HSP70 pathway.[J].Cellular and Molecular Neurobiology,2017,37(6):1105-1114.
[6] BERG Z H,ALLMANN D W,GIBSON D M.Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and with protein fractions of rat liver cytosol.Biochem Biophys Res Commun,1973,54(4):1362-1369.
[7] CARLSON C A,KIM K H.Regulation of hepatic acetyl coenzyme A carboxylase by phosphorylation and dephosphorylation[J].J Biol Chem,1973,248(1):378-380.
[8] YEH L A,LEE K H,KIM K H.Regulation of rat liver acetyl-CoA carboxylase.Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by the adenylate energy charge[J].J Biol Chem,1980,255(6):2308-2314.
[9] CARLING D,ZAMMIT V A,HARDIE D G.A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis[J].FEBS Lett,1987,223(2):217-222.
[10] YANG L,SHEN L,GAO P,et al.Effect of AMPK signal pathway on pathogenesis of abdominal aorticaneurysms[J].Oncotarget,2017,8(54):92827-92840.
[11] ZHANG C S,JIANG B,LI M,et al.The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1,acting as a switch between catabolism and anabolism[J].Cell Metab,2014,20(3):526-540.
[12] HARDIE D G.AMPK:positive and negative regulation,and its role in whole-body energy homeostasis[J].Current Opinion in Cell Biology,2015,33(33):1-7.
[13] ANDRIS F,LEO O.AMPK in lymphocyte metabolism and function[J].Int Rev Immunol,2015,34(1):67-81.
[14] ROSS F A,MACKINTOSH C,HARDIE D G.AMP-activated protein kinase:a cellular energy sensor that comes in 12 flavours[J].FEBS J,2016,283(16):2987-3001.
[15] OAKHILL J S,SCOTT J W,KEMP B E.AMPK functions as an adenylate charge-regulated protein kinase[J].Trends Endocrinol Metab,2012,23(3):125-132.
[16] WINDER WW,WILSON H A,HARDIE D G,et al.Phosphorylation of rat muscle acetyl-CoA carboxylase by AMP-activated protein kinase and protein kinase A[J].J Appl Physiol (1985),1997,82(1):219-225.
[17] ZHOU G,MYERS R,LI Y,et al.Role of AMP-activated protein kinase in mechanism of metformin action[J].J Clin Invest,2001,108(8):1167-1174.
[18] KOHJIMA M,HIGUCHI N,KATO M,et al.SREBP-1c,regulated by the insulin and AMPK signaling pathways,plays a role in nonalcoholic fatty liver disease[J].Int J Mol Med,2008,21(4):507-511.
[19] CORTON J M,GILLESPIE J G,HAWLEY S A,et al.5-aminoimidazole-4-carboxamide ribonucleoside.A specific method for activating AMP-activated protein kinase in intact cells?[J].Eur J Biochem,1995,229(2):558-565.
[20] KRAMER H F,WITCZAK C A,FUJII N,et al.Distinct signals regulate AS160 phosphorylation in response to insulin,AICAR,and contraction in mouse skeletal muscle.Diabetes,2006,55(7):2067-2076.
[21] TREEBAK J T,GLUND S,DESHMUKH A,et al.AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits[J].Diabetes,2006,55(7):2051-2058.
[22] ABDELAZIM A,KHATER S,ALI H,et al.Panax ginseng improves glucose metabolism in streptozotocin-induced diabetic rats through 5'Adenosine monophosphate kinase up-regulation[J].Saudi J Biol Sci,2018,(6).
[23] RABINOVITCH R,SAMBORSKA B,FAUBERT B,et al.AMPK maintains cellular metabolic homeostasis through regulation of mitochondrial reactive oxygen species[J].Cell Reports,2017,21(1):1-9.
[24] O'NEILL H M,HOLLOWAY G P,STEINBERG G R.AMPK regula-tion of fatty acid metabolism and mitochondrial biogenesis:implications for obesity[J].Mol Cell Endocrinol,2013,366(2):135-151.
[25] WEI J,FANG M,FU Z,et al.Sestrin 2 suppresses cells proliferation through AMPK/mTORC1 pathway activation in colorectal cancer[J].Oncotarget,2017,8(30):49318-49328.
[26] CAI Z,YANG B,SHI Y,et al.High glucose downregulates the effects of autophagy on osteoclastogenesis via the AMPK/mTOR/ULK1 pathway[J].Biochemical and Biophysical Research Communications,2018,503(2):428-435.
[27] 杜晨阳,王振,宋虎,等.AMPK通过调控mTOR/Nix信号通路参与小鼠肝缺血-再灌注损伤[J].中国普外基础与临床杂志,2017,(10):29-37.
[28] 董海平,周薇,王震虹,等.右美托咪定预处理经AMPK/SIRT1通路抑制大鼠脑缺血再灌注损伤的炎性反应[J].中国医药导报,2018,(1):4-9.
[29] JING H,YAO J,LIU X,et al.Fish-oil emulsion (omega-3 polyunsaturated fatty acids) attenuates acute lung injury induced by intestinal ischemia-reperfusion through Adenosine 5'-monophosphate-activated protein kinase-sirtuin1 pathway[J].Journal of Surgical Research,2014,187(1):252-261.
[30] MUGHAL W,DHINGRA R,KIRSHENBAUM L A.Striking a balance:autophagy,apoptosis,and necrosis in a normal and failing heart[J].Current Hypertension Reports,2012,14(6):540-547.
[31] XIE H,XU Q,JIA J,et al.Hydrogen sulfide protects against myocardial ischemia and reperfusion injury by activating AMP-activated protein kinase to restore autophagic flux[J].Biochemical and Biophysical Research Communications,2015,458(3):632-638.
[32] GUO H,ZHAO L,WANG B,et al.Remote limb ischemic postconditioning protects against cerebral ischemia-reperfusion injury by activating AMPK-dependent autophagy[J].Brain Research Bulletin,2018:S0361923017306056.
[33] WANG J F,MEI Z G,FU Y,et al.Puerarin protects rat brain against ischemia/reperfusion injury by suppressing autophagy via the AMPK-mTOR-ULK1 signaling pathway[J].Neural Regeneration Research,2018,13(6):989.
[34] ZHANG M,YANG D,GONG X,et al.Protective benefits of AMP-activated protein kinase in hepatic ischemia-reperfusion injury[J].Am J Transl Res,2017,9(3):823-829.
[35] ZAOUALI M A,BONCOMPAGNI E,REITER R J,et al.AMPK involvement in endoplasmic reticulum stress and autophagy modulation after fatty liver graft preservation:a role for melatonin and trimetazidine cocktail[J].Journal of Pineal Research,2013,55(1):65-78.
[36] PU T,LIAO X H,SUN H,et al.Augmenter of liver regeneration regulates autophagy in renal ischemia-reperfusion injury via the AMPK/mTOR pathway[J].Apoptosis,2017,22(7):955-969.

服务与反馈：

【文章下载】【发表评论】【查看评论】【加入收藏】

提示：您还未登录，请登录！点此登录