Nrf2-ARE通路在离体鼠心缺血/吡那地尔后处理中作用的研究
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摘要
目的：建立大鼠Langendorff离体心脏缺血再灌注(IRI)损伤模型,观察缺血/吡那地尔后处理对离体大鼠心功能的影响,并探讨核因子相关因子2(Nrf2)-抗氧化反应元件(ARE)通路在后处理心肌保护机制中的作用。
方法：采用Langendorff灌注装置,将56只雄性SD大鼠随机分为正常组(N组)、缺血再灌注损伤组(C组)、缺血后处理组(IPO组)、不同浓度的吡那地尔后处理组(5、10、30、50μM；P组),每组8例。N组：平衡灌注20min后,续灌100min；C组：平衡灌注20min,灌注4℃ST.Thomas停跳液,全心缺血40min,复灌60min; IPO组：离体心脏平衡灌注20min,全心缺血40min,再灌注开始给予6次间隔有氧灌注10s及全心缺血10s,续灌58min; P组：离体心脏平衡灌注20min,全心缺血40min,再灌注前给予含不同吡那地尔浓度的K-H液5min,续灌55min。记录各组平衡末及灌注末发展压(LVDP)、心率(HR)、舒张末压(LVEDP)、压力瞬时最小、最大变化率(±dp/dtmax)及率压双乘积(DP)来反映心功能；于灌注末取左心室心肌组织,分别采用RT-PCR和Western blotting方法,检测各组心肌组织中Nrf2、醌氧化还原酶(NQO1)、超氧化物歧化酶1(SOD1)及血红素加氧酶1(HO-1)基因mRNA转录及蛋白质表达的情况。
结果：
1.心功能指标：平衡末各组间心功能无明显差异(P>0.05)；在续灌末,N组、IPO组、P30、50μM组心功能显著优于C组及P5gM组(P<0.05或P<0.01),P10μM组在LVDP、LVEDP、-dp/dtmax方面显著优与P5μM组(P<0.05或P<0.01),P5μM组LVDP、LVEDP及+dp/dtmax显著优于C组(P<0.05或P<0.01),吡那地尔后处理在本实验浓度范围内呈浓度依赖关系恢复了缺血心肌的各心功能指标。
2. Nrf2、NQO1、SOD1及HO-1 mRNA表达量：与正常组相比,其他各组Nrf2、NQO1、SOD1及HO-1基因mRNA表达量均显著增高(P<0.05或P<0.01),吡那地尔后处理在本实验浓度范围内呈浓度依赖性地诱导了Nrf2及其下游基因mRNA表达量。Nrf2基因mRNA表达量在IPO组及P30、50μM组显著高于其他组(P<0.05或P<0.01)且三组之间无显著差异；SODl基因mRNA表达量在IPO组及P50gM组显著高于C组及P5gM组(P<0.05),P30μM显著高于C组(P<0.05)；NQO1基因mRNA表达量在C组、IPO组及各个浓度吡那地尔后处理组之间无显著差异(P>0.05)；HO-1基因mRNA转录量在IPO组、P50pM组显著高于C组及P5gM组(P<0.05或P<0.01)。
3.Nrf2、NQO1、SOD1及HO-1蛋白表达量：与N组相比,其他各组Nrf2、NQO1、SOD1及HO-1基因蛋白表达量显著增高(P<0.01),吡那地尔后处理在本实验浓度范围内呈浓度依赖性地诱导了Nrf2及其下游基因蛋白表达量。Nrf2及NQO1基因蛋白表达量在IPO及P30、50μM组显著高于其他组(P<0.05或P<0.01),P5、10μM组与C组之间无显著差异。HO-1及SOD1蛋白表达量在IPO及P30、50μM组显著高于C组及P5μM组(P<0.01)；SOD1蛋白表达量在P10μM组显著高于P5μM组(P<0.05)。
结论：
1、缺血后处理能改善缺血心肌的心功能,其心肌保护机制可能是激活了Nrf2-ARE通路,激活Nrf2-ARE通路可能是缺血后处理的心肌保护机制之一。
2、吡那地尔后处理可模拟缺血后处理对离体灌注心脏的心功能产生一定的保护作用,并实验所用浓度范围内有心肌保护的量效关系。
3、吡那地尔后处理可诱导Nrf2活化并诱导其下游抗氧化蛋白和二相解毒酶基因的mRNA及蛋白质上调表达,并在一定浓度范围内呈量效依赖关系。
4、IRI可以引起Nrf2基因的表达上调,继而上调抗氧化酶基因的表达。
Objective:To investigate the effect of ischemia or pinacidil postconditioning on function of Langendorff perfused rat hearts,and to explore the protective mechanisms of Nuclear factor-E2 related factor2(Nrf2)-Antioxidant response element(ARE) pathway on postconditioning.
Methods:56 Langendorff-perfused isolated Sprague-Dawley male rat hearts were divided into 7 groups (n=8, each group). After 20 min equilibration ischemia (40 min)/reperfusion (60 min) (I/R) was induced(group C), rat hearts were perfused with Krebs-Henseleit buffer containing different concentrations of pinacidil (5,10,30,50μM) for 5 min(group P) or subjected to six 10s cycles of ischemia/reperfusion(group IPO) at the beginning of reperfusion, the hearts were then reperfused for 55 or 58 min. Normal hearts were left untreated. Heart function was assessed by developed pressure (LVDP),±dp/dtmax, DP, heart rate (HR) and left ventricular end-diastolic pressure (LVEDP) at the point of equilibration and reperfusion end. To detect the gene and protein expression of Nrf2, quinone oxidoreductase 1(NQO1), Heme oxygenase 1(HO-1) and superoxide dismutase 1(SOD1) of the samples from left ventricle obtained after reperfusion, we used the methods of RT-PCR and Western blotting.
Results:
1. The cardiac function index There was no obvious difference in the cardiac function between each group after equilibrium (P> 0.05). After reperfusion, the cardiac function in group N, IPO, P(30,50μM) were obviously better than group C and P5μM (P<0.01 or 0.05), group PlOμM were obviously better than group P5μM on LVDP,-dp/dtmax and LVEDP (P<0.01 or 0.05) while group P5μM were obviously better than group C on LVDP,+ dp/dtmax and LVEDP (P<0.01 or 0.05). Ischemia hearts treated with pinacidil improved cardiac function in a concentration-dependent manner.
2. The mRNA expressions of Nrf2, HO-1, SOD1 and NQO1 The mRNA expressions of Nrf2, HO-1, SOD1 and NQO1 in group C, IPO, P(5,10,30,50μM) were obviously higher than group N (P<0.01 or 0.05). The mRNA expressions of Nrf2, HO-1, SOD1 and NQO1 were induced in pinacidil-treated hearts in a concentration-dependent manner. Nrf2:The mRNA expressions in group IPO, P(30, P50μM) were obviously higher than other groups (P<0.01 or 0.05) and there were no obvious difference between them. SOD1:The mRNA expressions in group IPO, P50μM were obviously higher than group C and P5μM (P<0.01 or 0.05), P30μM were obviously higher than group C (P< 0.05). NQO1:The mRNA expressions in group C, IPO, P(5,10,30,50μM) were no obviously difference(P>0.05). HO-1:The mRNA expressions in group IPO, P50μM were obviously higher than group C and P5μM (P<0.01 or 0.05).
3. The protein expressions of Nrf2, HO-1, SOD1 and NQO1 The protein expressions of Nrf2, HO-1, SOD1 and NQO1 in group C, IPO, P(5,10,30,50μM) were obviously higher than group N (P<0.01). The protein expressions of Nrf2, HO-1, SOD1 and NQO1 were induced in pinacidil-treated hearts in a concentration-dependent manner. Nrf2 and NQO1: The protein expressions in group IPO, P(30,50μM) were obviously higer than other groups (P<0.01 or 0.05), the protein expressions in group C, P(5, 10μM) were no obvious difference (P>0.05). HO-1 and SOD1:The protein expressions of HO-1 and SOD1 in group IPO, P(30,50μM) were obviously higer than group C and P5μM (P<0.01 or 0.05), the protein expressions of SOD1 in group P10μM were obviously higer than group P5μM (P<0.05).
Conclusion:Ischemia or pinacidil postconditioning could relieve ischemia reperfusion injury of isolated ischemia hearts, pinacidil could improve the cardiac function in a concentration-dependent manner in this experiment. Nrf2 which could upregulate antioxidants contributed to the effect of myocardial protection produced by ischemia or pinacidil postconditioning, and both mRNA and protein expression of Nrf2 and antioxidants are induced in pinacidil-treated hearts in a concentration-dependent fashion, the protective mechanisms of postconditioning may be partly mediated by Nrf2 activation, and then upregulate antioxidants through Nrf2-ARE pathway. Ischemia reperfusion may activate Nrf2-ARE pathway to survive ischemia myocardium.
方法：采用Langendorff灌注装置,将56只雄性SD大鼠随机分为正常组(N组)、缺血再灌注损伤组(C组)、缺血后处理组(IPO组)、不同浓度的吡那地尔后处理组(5、10、30、50μM；P组),每组8例。N组：平衡灌注20min后,续灌100min；C组：平衡灌注20min,灌注4℃ST.Thomas停跳液,全心缺血40min,复灌60min; IPO组：离体心脏平衡灌注20min,全心缺血40min,再灌注开始给予6次间隔有氧灌注10s及全心缺血10s,续灌58min; P组：离体心脏平衡灌注20min,全心缺血40min,再灌注前给予含不同吡那地尔浓度的K-H液5min,续灌55min。记录各组平衡末及灌注末发展压(LVDP)、心率(HR)、舒张末压(LVEDP)、压力瞬时最小、最大变化率(±dp/dtmax)及率压双乘积(DP)来反映心功能；于灌注末取左心室心肌组织,分别采用RT-PCR和Western blotting方法,检测各组心肌组织中Nrf2、醌氧化还原酶(NQO1)、超氧化物歧化酶1(SOD1)及血红素加氧酶1(HO-1)基因mRNA转录及蛋白质表达的情况。
结果：
1.心功能指标：平衡末各组间心功能无明显差异(P>0.05)；在续灌末,N组、IPO组、P30、50μM组心功能显著优于C组及P5gM组(P<0.05或P<0.01),P10μM组在LVDP、LVEDP、-dp/dtmax方面显著优与P5μM组(P<0.05或P<0.01),P5μM组LVDP、LVEDP及+dp/dtmax显著优于C组(P<0.05或P<0.01),吡那地尔后处理在本实验浓度范围内呈浓度依赖关系恢复了缺血心肌的各心功能指标。
2. Nrf2、NQO1、SOD1及HO-1 mRNA表达量：与正常组相比,其他各组Nrf2、NQO1、SOD1及HO-1基因mRNA表达量均显著增高(P<0.05或P<0.01),吡那地尔后处理在本实验浓度范围内呈浓度依赖性地诱导了Nrf2及其下游基因mRNA表达量。Nrf2基因mRNA表达量在IPO组及P30、50μM组显著高于其他组(P<0.05或P<0.01)且三组之间无显著差异；SODl基因mRNA表达量在IPO组及P50gM组显著高于C组及P5gM组(P<0.05),P30μM显著高于C组(P<0.05)；NQO1基因mRNA表达量在C组、IPO组及各个浓度吡那地尔后处理组之间无显著差异(P>0.05)；HO-1基因mRNA转录量在IPO组、P50pM组显著高于C组及P5gM组(P<0.05或P<0.01)。
3.Nrf2、NQO1、SOD1及HO-1蛋白表达量：与N组相比,其他各组Nrf2、NQO1、SOD1及HO-1基因蛋白表达量显著增高(P<0.01),吡那地尔后处理在本实验浓度范围内呈浓度依赖性地诱导了Nrf2及其下游基因蛋白表达量。Nrf2及NQO1基因蛋白表达量在IPO及P30、50μM组显著高于其他组(P<0.05或P<0.01),P5、10μM组与C组之间无显著差异。HO-1及SOD1蛋白表达量在IPO及P30、50μM组显著高于C组及P5μM组(P<0.01)；SOD1蛋白表达量在P10μM组显著高于P5μM组(P<0.05)。
结论：
1、缺血后处理能改善缺血心肌的心功能,其心肌保护机制可能是激活了Nrf2-ARE通路,激活Nrf2-ARE通路可能是缺血后处理的心肌保护机制之一。
2、吡那地尔后处理可模拟缺血后处理对离体灌注心脏的心功能产生一定的保护作用,并实验所用浓度范围内有心肌保护的量效关系。
3、吡那地尔后处理可诱导Nrf2活化并诱导其下游抗氧化蛋白和二相解毒酶基因的mRNA及蛋白质上调表达,并在一定浓度范围内呈量效依赖关系。
4、IRI可以引起Nrf2基因的表达上调,继而上调抗氧化酶基因的表达。
Objective:To investigate the effect of ischemia or pinacidil postconditioning on function of Langendorff perfused rat hearts,and to explore the protective mechanisms of Nuclear factor-E2 related factor2(Nrf2)-Antioxidant response element(ARE) pathway on postconditioning.
Methods:56 Langendorff-perfused isolated Sprague-Dawley male rat hearts were divided into 7 groups (n=8, each group). After 20 min equilibration ischemia (40 min)/reperfusion (60 min) (I/R) was induced(group C), rat hearts were perfused with Krebs-Henseleit buffer containing different concentrations of pinacidil (5,10,30,50μM) for 5 min(group P) or subjected to six 10s cycles of ischemia/reperfusion(group IPO) at the beginning of reperfusion, the hearts were then reperfused for 55 or 58 min. Normal hearts were left untreated. Heart function was assessed by developed pressure (LVDP),±dp/dtmax, DP, heart rate (HR) and left ventricular end-diastolic pressure (LVEDP) at the point of equilibration and reperfusion end. To detect the gene and protein expression of Nrf2, quinone oxidoreductase 1(NQO1), Heme oxygenase 1(HO-1) and superoxide dismutase 1(SOD1) of the samples from left ventricle obtained after reperfusion, we used the methods of RT-PCR and Western blotting.
Results:
1. The cardiac function index There was no obvious difference in the cardiac function between each group after equilibrium (P> 0.05). After reperfusion, the cardiac function in group N, IPO, P(30,50μM) were obviously better than group C and P5μM (P<0.01 or 0.05), group PlOμM were obviously better than group P5μM on LVDP,-dp/dtmax and LVEDP (P<0.01 or 0.05) while group P5μM were obviously better than group C on LVDP,+ dp/dtmax and LVEDP (P<0.01 or 0.05). Ischemia hearts treated with pinacidil improved cardiac function in a concentration-dependent manner.
2. The mRNA expressions of Nrf2, HO-1, SOD1 and NQO1 The mRNA expressions of Nrf2, HO-1, SOD1 and NQO1 in group C, IPO, P(5,10,30,50μM) were obviously higher than group N (P<0.01 or 0.05). The mRNA expressions of Nrf2, HO-1, SOD1 and NQO1 were induced in pinacidil-treated hearts in a concentration-dependent manner. Nrf2:The mRNA expressions in group IPO, P(30, P50μM) were obviously higher than other groups (P<0.01 or 0.05) and there were no obvious difference between them. SOD1:The mRNA expressions in group IPO, P50μM were obviously higher than group C and P5μM (P<0.01 or 0.05), P30μM were obviously higher than group C (P< 0.05). NQO1:The mRNA expressions in group C, IPO, P(5,10,30,50μM) were no obviously difference(P>0.05). HO-1:The mRNA expressions in group IPO, P50μM were obviously higher than group C and P5μM (P<0.01 or 0.05).
3. The protein expressions of Nrf2, HO-1, SOD1 and NQO1 The protein expressions of Nrf2, HO-1, SOD1 and NQO1 in group C, IPO, P(5,10,30,50μM) were obviously higher than group N (P<0.01). The protein expressions of Nrf2, HO-1, SOD1 and NQO1 were induced in pinacidil-treated hearts in a concentration-dependent manner. Nrf2 and NQO1: The protein expressions in group IPO, P(30,50μM) were obviously higer than other groups (P<0.01 or 0.05), the protein expressions in group C, P(5, 10μM) were no obvious difference (P>0.05). HO-1 and SOD1:The protein expressions of HO-1 and SOD1 in group IPO, P(30,50μM) were obviously higer than group C and P5μM (P<0.01 or 0.05), the protein expressions of SOD1 in group P10μM were obviously higer than group P5μM (P<0.05).
Conclusion:Ischemia or pinacidil postconditioning could relieve ischemia reperfusion injury of isolated ischemia hearts, pinacidil could improve the cardiac function in a concentration-dependent manner in this experiment. Nrf2 which could upregulate antioxidants contributed to the effect of myocardial protection produced by ischemia or pinacidil postconditioning, and both mRNA and protein expression of Nrf2 and antioxidants are induced in pinacidil-treated hearts in a concentration-dependent fashion, the protective mechanisms of postconditioning may be partly mediated by Nrf2 activation, and then upregulate antioxidants through Nrf2-ARE pathway. Ischemia reperfusion may activate Nrf2-ARE pathway to survive ischemia myocardium.
引文
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[38]Kobayashi M, Li L, Iwamoto N. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol,2009,29(2):493-502.
[39]Jinqing Li, Tomonaga Ichikawa, Joseph S Janicki. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets,2009,13(7):785-794.
[40]Zhu H, Itoh K, Yamamoto M, et al. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts:protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett,2005,579 (14):3029-3036.
[41]Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol, 2008,8 (2):71-85.
[42]Cao Z, Zhu H, Zhang L, et al. Antioxidants and phase 2 enzymes in cardiomyocytes: Chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfusion injury. Exp Biol Med,2006,231 (8):1353-1364.
[43]Dreger H, Westphal K, Weller A, et al. Nrf2-dependent upregulation of antioxidative enzymes:a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res,2009,83(2):354-361.
[44]Yun Y, Duan WG, Chen P, et al. Ischemic postconditioning modified renal oxidative stress and lipid peroxidation caused by ischemic reperfusion injury in rats. Transplant Proc, 2009,41 (9):3597-3602.
[45]Zeng Z, Huang HF, Chen MQ, et al. Postconditioning prevents ischemia/reperfusion injury in rat liver transplantation. Hepatogastroenterology,2010,57(101):875-881.
[46]张宗泽,程怡,王成夭,等.缺血后处理对心肌缺血/再灌注大鼠血红素加氧酶-1表达的影响.武汉大学学报,2008,29(3)309-311.
[47]Kabe Y, Ando K, Hirao S, et al. Redox regulation of NF-kappaB activation:distinct redox regulation between the cytoplasm and the nucleus. J Antioxid Redox Signal,2005,7 (3-4):395-403.
[48]Purdom-Dickinson SE, Lin Y, Dedek M, et al. Induction of antioxidant and detoxification response by oxidants in cardiomyocytes:evidence from gene expression profiling and activation of Nrf2 transcription factor. J Mol Cell Cardiol,2007,42 (1):159-176.
[49]Leonard MO, Kieran NE, Howell K. Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. J FASEB,2006,20(14):2624-2626.
[50]Liu M, Grigoryev DN, Crow MT. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int,2009,76(3):277-285.
[51]Yasuo M. Tsutsumi, Takaakira. Reactive oxygen species trigger ischemic and pharmacological postconditioning:in vivo and in vitro characterization. Life Sci,2007,81 (15):1223-1227.
[52]Lemoine S, Puddu PE, Durand C. Signaling pathways involved in postconditioning induced cardioprotection of human myocardium, in vitro. Exp Biol Med,2010,235(6):768-776.
[53]Penna C, Mancardi D, Rastaldo R. Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling. Cardiovasc Res,2007,75(1):168-177.
[54]Obal D, Dettwiler S, Favoccia C. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo.Anesth Analg,2005,101(5):1252-1260.
[55]Angeloni C, Leoncini E, Malaguti M. Modulation of phase Ⅱ enzymes by sulforaphane: implications for its cardioprotective potential. J Agric Food Chem,2009,57: 5615-5622.
[56]Saltman AE, Krukenkamp IB, Gaudette GR. Pharmacological Preconditioning With the Adenosine Triphosphate-Sensitive Potassium Channel Opener Pinacidil. Ann Thorac Surg,2000,70(2):595-601.
[57]Yang L, Yu T. Prolonged donor heart preservation with pinacidil:the role of mitochondria and the mitochondrial adenosine triphosphate-sensitive potassium channel. J Thorac Cardiovasc Surg,2010,139(4):1057-1063.
[58]Andrukhiv A, Costa AD, West IC. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol,2006,291(5):2067-2074.
[59]Penna C, Mancardi D, Raimondo S. The paradigm of postconditioning to protect the heart. J Cell Mol Med,2008,12(2):435-458.
[60]Kukreja RC. Mechanism of reactive oxygen species generation after opening of mitochondrial KATP channel. Am J Physiol Heart Circ Physiol,2006,291(5):2041-2043.
[1]Derek M, Yellon DS. Myocardial Reperfusion Injury. N Engl JMed,2007,357:1121-1135.
[2]Zweier JL. Measurement of superoxide-derived free radicals in the reperfused heart: evidence for a free radical mechanismof reperfusion injury. J Biol Chem,1988,263:1353-1357.
[3]Jinqing Li, Tomonaga Ichikawa, Joseph S Janicki. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets,2009,13(7):785-794.
[4]Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem,1991,266(18):11632-11639.
[5]Giudice A, Arra C, Turco MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol,2010,647:37-74.
[6]Furukawa M, Xiong Y. BTB protein Keapl targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Rocl ligase. Mol Cell Biol,2005,25 (1):162-171.
[7]Yamamoto T, Suzuki T, Kobayashi A. Physiological significance of reactive cysteine residues of Keapl in determining Nrf2 activity. Mol Cell Biol,2008,28 (8):2758-2770.
[8]Kang, M. I, Kobayashi, A, Wakabayashi, N, et al. Scaffolding ofKeapl to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A,2004,101,2046-2051.
[9]Kobayashi M, Itoh K, Suzuki T, et al. Identification of t he interactive interface and phylogenic conservation oft he Nrf2-Keapl system. Genes Cell s,2002,7:802-807.
[10]Hong, F, Freeman, M. L, and Liebler, D. C. Identification of sensor cysteines in human Keapl modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol,2005,18,1917-1926.
[11]Sherratt P J, Huang H C, Nguyen T, et al. Role of protein phosphorylation in the regulation of NF2E2-related factor 2 activity. Met hods Enzymol,2004,378:286-301.
[12]Jain AK, Bloom DA, Jaiswal AK. Nuclear import and export signals in control of Nrf2. J Biol Chem,2005,280(32):29158-29168.
[13]Tanigawa S, Fujii M, Hou DX. Action of Nrf2 and Keapl in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med,2007,42 (11):1690-1703.
[14]Talalay P, De Long MJ, Prochaska HJ. Identification of a common chemical signal regulating the induction of enz-ymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA,1988,85 (21):8261-8265.
[15]Jinqing Li, Tomonaga Ichikawa, Joseph S Janicki. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets,2009,13(7):785-794.
[16]Zhu H, Itoh K, Yamamoto M, et al. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts:protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett,2005,579 (14):3029-3036.
[17]Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol, 2008,8 (2):71-85.
[18]Cao Z, Zhu H, Zhang L, et al. Antioxidants and phase 2 enzymes in cardiomyocytes: Chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfusion injury. Exp Biol Med,2006,231(8):1353-1364.
[19]Dreger H, Westphal K, Weller A. Nrf2-dependent upregulation of antioxidative enzymes:a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res,2009,83(2):354-361.
[20]Dreger H, Westphal K, Wilck N. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res,2010,85(2):395-403.
[21]Piao CS, Gao S, Lee GH. Sulforaphane protects ischemic injury of hearts through antioxidant pathway and mitochondrial K(ATP) channels. Pharmacol Res,2010,61(4): 342-348.
[22]Angeloni C, Leoncini E, Malaguti M. Modulation of phase Ⅱ enzymes by sulforaphane:implications for its cardioprotective potential. J Agric Food Chem,2009,57 :5615-5622.
[23]Chen XL, Dodd G, Thomas S. Activation of Nrf2-ARE pathway protects endothelial cells from oxidantinjury and inhibits inflammatory gene expression. Am J Physiol Heart Circ Physiol,2006,290(5):1862-1870.
[24]Chen XL, Dodd G, Kunsch C. Sulforaphane inhibits TNF-alpha-induced activation of p38 MAP kinase and VCAM-1 and MCP-1 expression in endothelial cells. Inflamm Res,2009,58(8):513-521.
[25]Zakkar M, Van der Heiden K, Luong le A. Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler Thromb Vasc Biol, 2009,29(11):1851-1857.
[26]Gurusamy N, Goswami S, Malik G. Oxidative injury induces selective rather than global inhibition of proteasomal activity. J Mol Cell Cardiol,2008,44(2):419-428.
[27]Purdom-Dickinson SE, Lin Y, Dedek M. Induction of antioxidant and detoxification response by oxidants in cardiomyocytes:evidence from gene expression profiling and activation of Nrf2 transcription factor. J Mol Cell Cardiol,2007,42(1):159-176.
[28]Purdom-Dickinson SE, Sheveleva EV, Sun H. Translational control of Nrf2 protein in activation of antioxidant response by oxidants. Mol Pharmacol,2007,72 (4):1074-1081.
[29]Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol, 2008,8 (2):71-85.
[30]Calvert JW, Jha S, Gundewar S. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res,2009,105(4):365-374.
[31]Leonard MO, Kieran NE, Howell K. Reoxygenation-specific activation of the antioxidanttranscription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. J FASEB,2006,20(14):2624-2626.
[32]程翅,喻田,刘兴奎.硫化氢后处理对大鼠心肌缺血再灌注时左心室收缩功能的影响.中华麻醉学杂志,2010,30(10)：1175-1178.
[33]刘冲,喻田.Nrf2在大鼠心肌缺血/药物后处理中的作用.2010,学位论文.
[2]Murry CE, Jennings RB, Reimer KA. Preconditioning with isichemia:a delay of lethal cell injury in ischemic myocardium. Circulation,1986,74:1124-1136.
[3]Zhao ZQ, Corvera JS, Halkos ME, et al. Inhabition of myocardial injury by ischemic postconditioning during reperfusion:comparision with preconditioning. AM J Physiol Heart Circ Physiol,2003,285:579-588.
[4]Xi L, Bader M, Zhao Z-Q, et al. Loss of myocardial ischemic postcondditioning in adenosine Al and bradykinin B2 receptors gene knockout mice. Circulation,2008,118: 32-37.
[5]Jin ZQ, Karliner JS, Vessey DA. Ischemic postconditioning protects isolated mouse hearts against ischemia/reperfusion injury via sphingosine kinase isoform-1 activation. Cardiovasc Res,2008,79:134-140.
[6]Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Cirulation,2005,112: 2143-2148.
[7]LIN Xiang-min, ZHANG Zhi-yong, WANG Le-feng, et al. Attenuation of tumor necrosis factor-a elevation and improved heart function by postconditioning for 60 seconds in patients with acute myocardial infarction. Chinese Medical Journal,2010,123(14):1833-1839.
[8]Garcia S, Henry TD, Wang YL, et al. Long-term follow-up of patients undergoing postconditioning during ST-elevation myocardial infarction. J Cardiovasc Transl Res,2011, 4(1):92-98.
[9]Xue F, Yang X, Zhang B, et al. Postconditioning the human heart in percutaneous coronary intervention. Clin Cardiol,2010,33(7):439-444.
[10]Feng J, Fischer G, Lucchinetti E, et al. Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning: role of protein kinase B/Akt signaling. Anesthesiology,2006,104(5):1004-1014.
[11]Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther,2006,11:55-63.
[12]Sun HY, Wanig NP, Halkos M, et al. postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis,2006,11:1583-1593.
[13]段忠心,刘兴奎,喻田.二氮嗪后处理对大鼠离体心脏缺血再灌注损伤的影响.中华麻醉学杂志,2010,30(10)：1163-1167.
[14]Lemoine S, Puddu PE, Durand C, et al. Signaling pathways involved in postconditioning-induced cardioprotection of human myocardium in vitro. Exp Biol Med, 2010,235(6):768-776.
[15]黄燕,刘兴奎,喻田等.吡那地尔预处理对兔心脏缺血再灌注时心肌炎性反应的影响.中华麻醉学杂志,2008,28：224-227.
[16]石金山,喻田.缺氧/药物后处理对大鼠心肌细胞ATP敏感性钾通道亚基的影响.2010,学位论文。
[17]Han J, Kim N, Park J. Opening of mitochondrial ATP-sensitive potassium channels evokes oxygen radical generation in rabbit heart slices. J Biochem,2002,131(5):721-727.
[18]Kim J K, Pedram A, Razandi M, et al. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem,2006,281 (10):6760-6767.
[19]Zhao ZQ. Oxidative stress elicited myocardial apoptosis during reperfusion. J Curr Opin Pharmacology,2004,4 (2):159-165.
[20]Danielisova V, Nemethova M, Gottlieb M, et al. The changes in endogenous antioxidant enzyme activity after postconditioning. Cell Mol Neurobiol,2006,26(7-8): 1181-1191.
[21]Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol,2004,37(2):139-143.
[22]Wasserman W W, Fahl W E. Functional antioxidant responsive elements. Proc Natl Acad Sci U S A,1997,94,5361-5366.
[23]Zhu H, Itoh K, Yamamoto M, et al. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts:protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett,2005,579 (14):3029-3036.
[24]Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol, 2008,8 (2):71-85.
[25]Cao Z, Zhu H, Zhang L, et al. Antioxidants and phase 2 enzymes in cardiomyocytes: Chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfu sion injury. Exp Biol Med,2006,231 (8):1353-1364.
[26]Piao CS, Gao S, Lee GH, et al. Sulforaphane protects ischemic injury of hearts through antioxidant pathway and mitochondrial K(ATP) channels. Pharmacol Res,2010,61 (4):342-348.
[27]John W,Calvert, Saurabh Jha, John W. Hydrogen Sulfide Mediates Cardioprotection Through Nrf2 Signaling. Circ. Res,2009,105:365-374.
[28]刘冲,喻田.Nrf2在大鼠心肌缺血/药物后处理中的作用.2010,学位论文.
[29]Lee DS, Steinbaugh GE, Quarrie R, et al. Ischemic postconditioning does not provide cardioprotection from long-term ischemic injury in isolated male or female rat hearts. J Surg Res,2010,164(2):175-181.
[30]Couvreur N, Lucats L, Tissier R, et al. Differential effects of postconditioning on myocardial stunning and infarction:a study in conscious dogs and anesthetized rabbits. Am J Physiol,2006,291:1345-1350.
[31]Vinten-Johansen J, Zhao ZQ, Jiang R, et al. Precondtioning and postconditioning: innate cardioprotection from ischemia reperfusion injury. J Appl Physiol,2007,103: 1441-1448.
[32]Yao YT, Fang NX, Shi CX, et al. Sevoflurane postconditioning protects isolated rat hearts against ischemia-reperfusion injury. J Chin Med,2010,123(10):1320-1328.
[33]程翅,喻田,刘兴奎.硫化氢后处理对大鼠心肌缺血再灌注时左心室收缩功能的影响.中华麻醉学杂志,2010,30(10)：1175-1178.
[34]Furukawa M, Xiong Y. BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase. Mol Cell Biol,2005,25 (1):162-171.
[35]Maruyama A, Nishikawa K, Kawatani Y. The novel NRF2-interacting factor KEAP1 regulates susceptibility to oxidative stress by promoting the NRF2-mediated cytoprotective response.J Biochem,2011,45(4):1074-1081.
[36]Purdom-Dickinson SE, Sheveleva EV, Sun H,et al. Translational control of Nrf2 protein in activation of antioxidant response by oxidants. Mol Pharmacol,2007,72(4): 1074-1081.
[37]Hong, F., Freeman, M. L., and Liebler, D. C. Identification of sensor cysteines in human Keapl modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol,2005,18,1917-1926.
[38]Kobayashi M, Li L, Iwamoto N. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol,2009,29(2):493-502.
[39]Jinqing Li, Tomonaga Ichikawa, Joseph S Janicki. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets,2009,13(7):785-794.
[40]Zhu H, Itoh K, Yamamoto M, et al. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts:protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett,2005,579 (14):3029-3036.
[41]Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol, 2008,8 (2):71-85.
[42]Cao Z, Zhu H, Zhang L, et al. Antioxidants and phase 2 enzymes in cardiomyocytes: Chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfusion injury. Exp Biol Med,2006,231 (8):1353-1364.
[43]Dreger H, Westphal K, Weller A, et al. Nrf2-dependent upregulation of antioxidative enzymes:a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res,2009,83(2):354-361.
[44]Yun Y, Duan WG, Chen P, et al. Ischemic postconditioning modified renal oxidative stress and lipid peroxidation caused by ischemic reperfusion injury in rats. Transplant Proc, 2009,41 (9):3597-3602.
[45]Zeng Z, Huang HF, Chen MQ, et al. Postconditioning prevents ischemia/reperfusion injury in rat liver transplantation. Hepatogastroenterology,2010,57(101):875-881.
[46]张宗泽,程怡,王成夭,等.缺血后处理对心肌缺血/再灌注大鼠血红素加氧酶-1表达的影响.武汉大学学报,2008,29(3)309-311.
[47]Kabe Y, Ando K, Hirao S, et al. Redox regulation of NF-kappaB activation:distinct redox regulation between the cytoplasm and the nucleus. J Antioxid Redox Signal,2005,7 (3-4):395-403.
[48]Purdom-Dickinson SE, Lin Y, Dedek M, et al. Induction of antioxidant and detoxification response by oxidants in cardiomyocytes:evidence from gene expression profiling and activation of Nrf2 transcription factor. J Mol Cell Cardiol,2007,42 (1):159-176.
[49]Leonard MO, Kieran NE, Howell K. Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury. J FASEB,2006,20(14):2624-2626.
[50]Liu M, Grigoryev DN, Crow MT. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int,2009,76(3):277-285.
[51]Yasuo M. Tsutsumi, Takaakira. Reactive oxygen species trigger ischemic and pharmacological postconditioning:in vivo and in vitro characterization. Life Sci,2007,81 (15):1223-1227.
[52]Lemoine S, Puddu PE, Durand C. Signaling pathways involved in postconditioning induced cardioprotection of human myocardium, in vitro. Exp Biol Med,2010,235(6):768-776.
[53]Penna C, Mancardi D, Rastaldo R. Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling. Cardiovasc Res,2007,75(1):168-177.
[54]Obal D, Dettwiler S, Favoccia C. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo.Anesth Analg,2005,101(5):1252-1260.
[55]Angeloni C, Leoncini E, Malaguti M. Modulation of phase Ⅱ enzymes by sulforaphane: implications for its cardioprotective potential. J Agric Food Chem,2009,57: 5615-5622.
[56]Saltman AE, Krukenkamp IB, Gaudette GR. Pharmacological Preconditioning With the Adenosine Triphosphate-Sensitive Potassium Channel Opener Pinacidil. Ann Thorac Surg,2000,70(2):595-601.
[57]Yang L, Yu T. Prolonged donor heart preservation with pinacidil:the role of mitochondria and the mitochondrial adenosine triphosphate-sensitive potassium channel. J Thorac Cardiovasc Surg,2010,139(4):1057-1063.
[58]Andrukhiv A, Costa AD, West IC. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol,2006,291(5):2067-2074.
[59]Penna C, Mancardi D, Raimondo S. The paradigm of postconditioning to protect the heart. J Cell Mol Med,2008,12(2):435-458.
[60]Kukreja RC. Mechanism of reactive oxygen species generation after opening of mitochondrial KATP channel. Am J Physiol Heart Circ Physiol,2006,291(5):2041-2043.
[1]Derek M, Yellon DS. Myocardial Reperfusion Injury. N Engl JMed,2007,357:1121-1135.
[2]Zweier JL. Measurement of superoxide-derived free radicals in the reperfused heart: evidence for a free radical mechanismof reperfusion injury. J Biol Chem,1988,263:1353-1357.
[3]Jinqing Li, Tomonaga Ichikawa, Joseph S Janicki. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets,2009,13(7):785-794.
[4]Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem,1991,266(18):11632-11639.
[5]Giudice A, Arra C, Turco MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol,2010,647:37-74.
[6]Furukawa M, Xiong Y. BTB protein Keapl targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Rocl ligase. Mol Cell Biol,2005,25 (1):162-171.
[7]Yamamoto T, Suzuki T, Kobayashi A. Physiological significance of reactive cysteine residues of Keapl in determining Nrf2 activity. Mol Cell Biol,2008,28 (8):2758-2770.
[8]Kang, M. I, Kobayashi, A, Wakabayashi, N, et al. Scaffolding ofKeapl to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A,2004,101,2046-2051.
[9]Kobayashi M, Itoh K, Suzuki T, et al. Identification of t he interactive interface and phylogenic conservation oft he Nrf2-Keapl system. Genes Cell s,2002,7:802-807.
[10]Hong, F, Freeman, M. L, and Liebler, D. C. Identification of sensor cysteines in human Keapl modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol,2005,18,1917-1926.
[11]Sherratt P J, Huang H C, Nguyen T, et al. Role of protein phosphorylation in the regulation of NF2E2-related factor 2 activity. Met hods Enzymol,2004,378:286-301.
[12]Jain AK, Bloom DA, Jaiswal AK. Nuclear import and export signals in control of Nrf2. J Biol Chem,2005,280(32):29158-29168.
[13]Tanigawa S, Fujii M, Hou DX. Action of Nrf2 and Keapl in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med,2007,42 (11):1690-1703.
[14]Talalay P, De Long MJ, Prochaska HJ. Identification of a common chemical signal regulating the induction of enz-ymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA,1988,85 (21):8261-8265.
[15]Jinqing Li, Tomonaga Ichikawa, Joseph S Janicki. Targeting the Nrf2 pathway against cardiovascular disease. Expert Opin Ther Targets,2009,13(7):785-794.
[16]Zhu H, Itoh K, Yamamoto M, et al. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts:protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett,2005,579 (14):3029-3036.
[17]Zhu H, Jia Z, Misra BR, et al. Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress. Cardiovasc Toxicol, 2008,8 (2):71-85.
[18]Cao Z, Zhu H, Zhang L, et al. Antioxidants and phase 2 enzymes in cardiomyocytes: Chemical inducibility and chemoprotection against oxidant and simulated ischemia-reperfusion injury. Exp Biol Med,2006,231(8):1353-1364.
[19]Dreger H, Westphal K, Weller A. Nrf2-dependent upregulation of antioxidative enzymes:a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res,2009,83(2):354-361.
[20]Dreger H, Westphal K, Wilck N. Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res,2010,85(2):395-403.
[21]Piao CS, Gao S, Lee GH. Sulforaphane protects ischemic injury of hearts through antioxidant pathway and mitochondrial K(ATP) channels. Pharmacol Res,2010,61(4): 342-348.
[22]Angeloni C, Leoncini E, Malaguti M. Modulation of phase Ⅱ enzymes by sulforaphane:implications for its cardioprotective potential. J Agric Food Chem,2009,57 :5615-5622.
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