缺血后处理对糖尿病大鼠缺血再灌注心肌细胞的影响及机制研究
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摘要
前言
急性心肌梗死是严重危害人类健康的常见疾病,其根本解决方法就是尽快恢复心肌的血液供应。随着静脉溶栓术、经皮冠状动脉腔内成形术等技术的广泛应用,缺血心肌能够重新获得血液供应,明显减轻了缺血性心肌损伤。但是,再灌注过程往往加重组织细胞功能代谢障碍及结构破坏,引起致命性损伤,即缺血／再灌注损伤(ischemia/reperfusion injury,I/RI)。
近年来,缺血后处理的心脏保护作用逐渐被人们重视,尽管作用机制仍在探讨之中,但其减轻I／RI的作用已经被广泛关注。作为一种内源性心脏保护机制,目前多个种系的动物实验已经证明PI3K/Akt信号通路参与了缺血后处理的心脏保护作用。
现今,糖尿病已成为严重危害人类健康的全球流行性疾病,其持续增长的流行病学趋势已成为严重的公共卫生问题,其慢性并发症是患者致残、致死的主要原因。与非糖尿病人群相比,糖尿病人群中动脉粥样硬化性疾病的患病率高、发病年龄轻、病情进展较快,多脏器同时受累较多。糖尿病人群心脑血管病患病率为非糖尿病人群的2～3倍。
本研究通过观察缺血后处理对糖尿病大鼠缺血再灌注心肌梗死面积、心肌细胞凋亡指数的变化,系统评价其对糖尿病大鼠心肌缺血再灌注损伤的影响；采用分子生物学的方法,观察缺血后处理对PI3K／Akt信号通路中的关键酶Akt及其下游调控的eNOS表达的影响,以探讨缺血后处理的心血管保护效应及其可能的分子机制,为缺血后处理广泛应用于临床提供理论依据。
材料与方法
一、实验材料
12周龄雄性SD大鼠72只,购于哈尔滨医科大学实验动物中心。分组干预后取血,并采集心肌标本。TUNEL凋亡检测试剂盒、p-Akt、Akt单克隆抗体、p-eNOS、eNOS单克隆抗体购于上海碧云天生物制剂有限公司；β-actin单克隆抗体、RT-PCR试剂盒购于日本TakaRa公司。
二、实验方法
(一)缺血后处理对糖尿病大鼠心肌缺血再灌注损伤的影响
经尾静脉注射链脲佐菌素溶液(45mg／kg)制备糖尿病大鼠模型,采用随机区组设计将大鼠分为4组：正常组：正常饲养；假手术组：前降支下只穿线,不结扎；缺血再灌注组：结扎前降支30min,再灌注2h；缺血后处理组：结扎前降支30min,再灌注前行缺血30s,再灌注30s共3个循环,再灌注2h。检测各组大鼠CK-MB、心肌梗死面积、心肌细胞凋亡指数。
(二)PI3K／Akt信号通路在糖尿病大鼠缺血再灌注心肌中的调控作用
在上述实验基础上增加缺血再灌注+渥曼青霉素组：结扎前降支30min,再灌注前5min经尾静脉注射渥曼青霉素(15μg／kg),再灌注2h；缺血后处理+渥曼青霉素组：结扎前降支30min,再灌注前5min经尾静脉注射渥曼青霉素(15μg/kg),再灌注前行缺血30s,再灌注30s共3个循环,再灌注2h。检测各组心肌梗死面积、心肌细胞凋亡指数。免疫组化技术检测各组大鼠心肌p-Akt, p-eNOS。RT-PCR方法检测各组大鼠心肌Akt,eNOS基因表达。Western blot方法检测各组大鼠心肌p-Akt, Akt, p-eNOS, eNOS蛋白表达。
三、统计学处理
采用SPSS16.0软件进行统计处理,各项观察指标均以均数±标准差(x±s)表示,多组间比较采用单因素方差分析(one-way ANOVA),两两比较采用SNK-q检验,以P<0.05作为有统计学意义的界值。
实验结果
一、缺血后处理对糖尿病大鼠心肌I／RI的影响
缺血后处理组大鼠心肌梗死面积、心肌细胞凋亡指数与缺血再灌注组大鼠比较明显减小,血清CK-MB水平减低(P<0.05)；应用PI3K/Akt信号通路抑制剂渥曼青霉素后,缺血后处理组大鼠心肌梗死面积、心肌细胞凋亡指数、血清CK-MB水平增加,与缺血再灌注组比较差异无显著性(p>0.05)。
二、各组大鼠心肌免疫组化染色p-Akt、p-eNOS的比较
缺血后处理组大鼠心肌免疫组化显示p-Akt、p-eNOS表达水平高于缺血再灌注组,应用PI3K/Akt信号通路抑制剂渥曼青霉素后,缺血后处理组大鼠心肌p-Akt、p-eNOS表达水平减低,与缺血再灌注组比较差异无显著性(P>0.05)。
三、Western blot检测各组大鼠心肌p-Akt/ Akt、p-eNOS/eNOS的比较
缺血后处理组大鼠心肌p-Akt／Akt、p-eNOS／eNOS表达水平高于缺血再灌注组,应用PI3K／Akt信号通路抑制剂渥曼青霉素后,缺血后处理组大鼠心肌p-Akt／Akt、p-eNOS／eNOS表达水平减低,与缺血再灌注组比较差异无显著性(P>0.05)。
四、RT-PCR检测各组大鼠心肌AktmRNA、eNOSmRNA的比较
各组大鼠心肌AktmRNA、eNOSmRNA的表达比较无统计学意义(P>0.05)。
结论
缺血后处理可以减轻糖尿病大鼠缺血再灌注心肌的梗死面积,减小凋亡指数,同时上调p-Akt、p-eNOS的表达,应用PI3K／Akt信号通路抑制剂渥曼青霉素后大鼠心肌p-Akt、p-eNOS的表达减少,同时缺血后处理的上述心脏保护作用消失,说明PI3K／Akt信号通路参与了缺血后处理对糖尿病大鼠缺血再灌注心肌的保护作用。
Introduction
Coronary heart disease is the main serious disease which is harmful to health, of them acute myocardial infarction (AMI) is the serious type. With the development of Intravenous thrombolysis、Percutaneous transluminal coronary angioplasty, ischemic myocardial injury was significantly reduced. But the reperfusion led to ischemia/reperfusion injury(I/RI). Ischemic postconditioning was proved to reduce I/RI through the PI3K/Akt pathway play a heart protective effect.
Diabetes has become a serious disease to human health. Atherosclerosis was main chronic complication. However, the cardioprotective effect and mechanism of ischemic postconditioning on atherosclerosis have not been verifed.
In the present experiment, we studied the effect on cardiovascular system and expression of Akt、eNOS in the heart of diabetic rats.
Materials and methods
SD rats(12-week-old males) were randomly divided into 6 groops of 8 rats each, Diabetic model was induced by Streptozotozin (STZ,45mg/kg):normal; sham; IR IPostC; IR+wortmannin; IPostC+wortmannin. The effects of IPostC on I/RI were evaluated by infarct size, apoptotic index, and gene expression analysis(p-Akt, Akt, p-eNOS, eNOS protein and mRNA expression).
Results
1、IPostC can reduce infarct size, apoptotic index.
2、IPostC can increase p-Akt, Akt, p-eNOS, eNOS protein and mRNA the expression.
3、With the wortmannin, the inhibitor of PI3K/Akt pathway, IPostC can not reduce infarct size, apoptotic index and the expression of p-Akt, Akt, p-eNOS, eNOS protein and mRNA were lessened.
Conclusion
IPostC has the certain protective effects on I/RI of diabetic rats. Wortmannin reduced the protective effects of IPostC. So the effects of IPostC on I/RI of diabetic rats may be mediated by the PI3K/Akt pathway.
急性心肌梗死是严重危害人类健康的常见疾病,其根本解决方法就是尽快恢复心肌的血液供应。随着静脉溶栓术、经皮冠状动脉腔内成形术等技术的广泛应用,缺血心肌能够重新获得血液供应,明显减轻了缺血性心肌损伤。但是,再灌注过程往往加重组织细胞功能代谢障碍及结构破坏,引起致命性损伤,即缺血／再灌注损伤(ischemia/reperfusion injury,I/RI)。
近年来,缺血后处理的心脏保护作用逐渐被人们重视,尽管作用机制仍在探讨之中,但其减轻I／RI的作用已经被广泛关注。作为一种内源性心脏保护机制,目前多个种系的动物实验已经证明PI3K/Akt信号通路参与了缺血后处理的心脏保护作用。
现今,糖尿病已成为严重危害人类健康的全球流行性疾病,其持续增长的流行病学趋势已成为严重的公共卫生问题,其慢性并发症是患者致残、致死的主要原因。与非糖尿病人群相比,糖尿病人群中动脉粥样硬化性疾病的患病率高、发病年龄轻、病情进展较快,多脏器同时受累较多。糖尿病人群心脑血管病患病率为非糖尿病人群的2～3倍。
本研究通过观察缺血后处理对糖尿病大鼠缺血再灌注心肌梗死面积、心肌细胞凋亡指数的变化,系统评价其对糖尿病大鼠心肌缺血再灌注损伤的影响；采用分子生物学的方法,观察缺血后处理对PI3K／Akt信号通路中的关键酶Akt及其下游调控的eNOS表达的影响,以探讨缺血后处理的心血管保护效应及其可能的分子机制,为缺血后处理广泛应用于临床提供理论依据。
材料与方法
一、实验材料
12周龄雄性SD大鼠72只,购于哈尔滨医科大学实验动物中心。分组干预后取血,并采集心肌标本。TUNEL凋亡检测试剂盒、p-Akt、Akt单克隆抗体、p-eNOS、eNOS单克隆抗体购于上海碧云天生物制剂有限公司；β-actin单克隆抗体、RT-PCR试剂盒购于日本TakaRa公司。
二、实验方法
(一)缺血后处理对糖尿病大鼠心肌缺血再灌注损伤的影响
经尾静脉注射链脲佐菌素溶液(45mg／kg)制备糖尿病大鼠模型,采用随机区组设计将大鼠分为4组：正常组：正常饲养；假手术组：前降支下只穿线,不结扎；缺血再灌注组：结扎前降支30min,再灌注2h；缺血后处理组：结扎前降支30min,再灌注前行缺血30s,再灌注30s共3个循环,再灌注2h。检测各组大鼠CK-MB、心肌梗死面积、心肌细胞凋亡指数。
(二)PI3K／Akt信号通路在糖尿病大鼠缺血再灌注心肌中的调控作用
在上述实验基础上增加缺血再灌注+渥曼青霉素组：结扎前降支30min,再灌注前5min经尾静脉注射渥曼青霉素(15μg／kg),再灌注2h；缺血后处理+渥曼青霉素组：结扎前降支30min,再灌注前5min经尾静脉注射渥曼青霉素(15μg/kg),再灌注前行缺血30s,再灌注30s共3个循环,再灌注2h。检测各组心肌梗死面积、心肌细胞凋亡指数。免疫组化技术检测各组大鼠心肌p-Akt, p-eNOS。RT-PCR方法检测各组大鼠心肌Akt,eNOS基因表达。Western blot方法检测各组大鼠心肌p-Akt, Akt, p-eNOS, eNOS蛋白表达。
三、统计学处理
采用SPSS16.0软件进行统计处理,各项观察指标均以均数±标准差(x±s)表示,多组间比较采用单因素方差分析(one-way ANOVA),两两比较采用SNK-q检验,以P<0.05作为有统计学意义的界值。
实验结果
一、缺血后处理对糖尿病大鼠心肌I／RI的影响
缺血后处理组大鼠心肌梗死面积、心肌细胞凋亡指数与缺血再灌注组大鼠比较明显减小,血清CK-MB水平减低(P<0.05)；应用PI3K/Akt信号通路抑制剂渥曼青霉素后,缺血后处理组大鼠心肌梗死面积、心肌细胞凋亡指数、血清CK-MB水平增加,与缺血再灌注组比较差异无显著性(p>0.05)。
二、各组大鼠心肌免疫组化染色p-Akt、p-eNOS的比较
缺血后处理组大鼠心肌免疫组化显示p-Akt、p-eNOS表达水平高于缺血再灌注组,应用PI3K/Akt信号通路抑制剂渥曼青霉素后,缺血后处理组大鼠心肌p-Akt、p-eNOS表达水平减低,与缺血再灌注组比较差异无显著性(P>0.05)。
三、Western blot检测各组大鼠心肌p-Akt/ Akt、p-eNOS/eNOS的比较
缺血后处理组大鼠心肌p-Akt／Akt、p-eNOS／eNOS表达水平高于缺血再灌注组,应用PI3K／Akt信号通路抑制剂渥曼青霉素后,缺血后处理组大鼠心肌p-Akt／Akt、p-eNOS／eNOS表达水平减低,与缺血再灌注组比较差异无显著性(P>0.05)。
四、RT-PCR检测各组大鼠心肌AktmRNA、eNOSmRNA的比较
各组大鼠心肌AktmRNA、eNOSmRNA的表达比较无统计学意义(P>0.05)。
结论
缺血后处理可以减轻糖尿病大鼠缺血再灌注心肌的梗死面积,减小凋亡指数,同时上调p-Akt、p-eNOS的表达,应用PI3K／Akt信号通路抑制剂渥曼青霉素后大鼠心肌p-Akt、p-eNOS的表达减少,同时缺血后处理的上述心脏保护作用消失,说明PI3K／Akt信号通路参与了缺血后处理对糖尿病大鼠缺血再灌注心肌的保护作用。
Introduction
Coronary heart disease is the main serious disease which is harmful to health, of them acute myocardial infarction (AMI) is the serious type. With the development of Intravenous thrombolysis、Percutaneous transluminal coronary angioplasty, ischemic myocardial injury was significantly reduced. But the reperfusion led to ischemia/reperfusion injury(I/RI). Ischemic postconditioning was proved to reduce I/RI through the PI3K/Akt pathway play a heart protective effect.
Diabetes has become a serious disease to human health. Atherosclerosis was main chronic complication. However, the cardioprotective effect and mechanism of ischemic postconditioning on atherosclerosis have not been verifed.
In the present experiment, we studied the effect on cardiovascular system and expression of Akt、eNOS in the heart of diabetic rats.
Materials and methods
SD rats(12-week-old males) were randomly divided into 6 groops of 8 rats each, Diabetic model was induced by Streptozotozin (STZ,45mg/kg):normal; sham; IR IPostC; IR+wortmannin; IPostC+wortmannin. The effects of IPostC on I/RI were evaluated by infarct size, apoptotic index, and gene expression analysis(p-Akt, Akt, p-eNOS, eNOS protein and mRNA expression).
Results
1、IPostC can reduce infarct size, apoptotic index.
2、IPostC can increase p-Akt, Akt, p-eNOS, eNOS protein and mRNA the expression.
3、With the wortmannin, the inhibitor of PI3K/Akt pathway, IPostC can not reduce infarct size, apoptotic index and the expression of p-Akt, Akt, p-eNOS, eNOS protein and mRNA were lessened.
Conclusion
IPostC has the certain protective effects on I/RI of diabetic rats. Wortmannin reduced the protective effects of IPostC. So the effects of IPostC on I/RI of diabetic rats may be mediated by the PI3K/Akt pathway.
引文
1 Murry CE, Jennings RB, Reimer KA, el al. Preconditioning with ischemia:A delay of lethal cell injury in ischemic myocardium.Circulation.1986;74:1124-1136.
2 Zhao ZQ. Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning.Am J Physiol Heart Circ Physiol.2003;285:H579-H 588.
3 Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulation blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation.Basic Res Cardiol.2005;100:57-63.
4 ZhaoJL, Yang YJ, You SJ, et al.Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic miniswines.Mierovasc Res.2007;73:137-142.
5 Scartabelli T,Gerace E,Landucci E,et al. Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-Akt signaling pathway:a novel postconditioning strategy?.Neuropharmacology.2008;55:509-516.
6 李立明,饶克勤,孔灵芝,等.中国居民营养与健康状况调查技术执行组.中国居民2002年营养与健康状况调查.中华流行病学杂志.2005；26：478-484.
7 American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes care.2007; 30:S42-47.
8 《中国糖尿病防治指南》编写组.中国糖尿病防治指南.北京大学医学出版社,2008.
9 Larosa JC,Grundy,Water DD, et al. Treating to New Targets (TNT) Investigators.Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med.2005; 352:1425-1435.
10 Van Domburg RT, Sonnenschein K, Nieuwlaat R, et al. Sustained benefit 20 years after reperfusion therapy in acute therapy in acute myocardial infarction.J Am Coll Cardiol. 2005;46:15-20.
11 Song WY,Dong HL,Cheng Q,et al.Ischemic postconditioning induces neuroprotection
via up-regulationof endogenous antioxidant enzyme activities experiment with rabbits. Zhonghua Yi Xue Za Zhi.2008,88:2355-2359.
12 Zhang YM, Wang Y, Liu XH. et al. Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/reperfusion injury:experiment with rat. Zhonghua Yi Xue Za Zhi.2008:88:2558-2561.
13 Wang KX,Hu SY,Jiang XS, et al.Protective effects of ischaemic postconditioning on warm/cold ischaemic reperfusion injury in rat liver:a comparative study with ischaemic preconditioning.Chin Med J.2008;121:2004-2009.
14 Somers S, Opie L, Lecour S. Sphingosine-1-phosphate (SIP) can mimic ischaemic postconditioning via activation of the JAK/STAT-3 pathway. Cardiovasc J Afr.2008;19: S33-34.
15 Lacerda L. TNF alpha signalling:a critical role in ischaemic postconditioning? Cardiobasc J Afr.2008;19:S17-18.
16 Yang XM, Proctor JB,Cui L,et al. Multiple brief coronary occlusion during early reperfusion protect rabbit hearts by targeting cell signal in pathways.J Am Coll cardiol.2004;44:1103-1110.
17 Kin H, Zhao ZQ, SunHY,et al. Postconditioning attenuates myocardial ischemia reperfusion injury by inhibiting events in the early minutes of reperfusion.Cardiovasc Res.2004; 62:74-85.
18 Yang XM, Proctor JB, Cui L, et al. Multiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways J Am Coll Cardiol.2004; 44:1103-1110.
19 Ravingerova T, Stetka R, Paneza D,et al. Susceptibility to isehemia-indueed arrhythmias and the effete of preeonditioning in the diabetic rat heart. Physiol Res.2000; 49:607-616.
20 Gross ER, Gross GJ. Ligand triggers of classical preconditioning and postconditioning. Cardiovasc Res.2006;70:212-221.
21 Mocanu MM, Baxter GF,Yellon DM.Caspase inhibition and limitation of myocardial infarct size:protection against lethal reperfusioninjury.Br J Pharmacol.2000; 130:197-200.
22 Zhao ZQ. Morris CD, Budde JM. et al.Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion. Cardiovasc Res 2003;59:132-142.
23 Argaud L, Gateau-Roesch, O, Raisky O, et al. Post-conditioning inhibits mitochondrial permeability transition.Circulation.2005; 111:194-197.
24 Tsang A, Hausenloy DJ, Macanu MM, et al. Postconditioning:A form of "modified reperfusion " protects the myocardium by activating the PI3K-Akt pathway[J].Circ Res.2004; 95:230-232.
25 Bopassa jc, Ferrera R,Gateau-Roesch O,el al.PI3-kinase regulates the mitochondrial transition pore in controlled reperfusion andpostconditioning.Cardiovasc Res.2006;69:178-185.
26 Won CK, Ha SJ, Noh HS, et al.Estradiol prevents the injury induced decrease of Akt activation and Bad phosphorylation. Neurosci lett.2005; 387:115-119.
27 Hwang IK.Yoo KY.Park SK, et al. Expression and changes of endogenous insulin-like growth factor-1 in neurons and gila in the gerbil hippocampus and dentate gyros after ischemic insult.Neuro-chem Int.2004;45:149-156.
28 Zhu Y, Culmsee C, Klumpp S, et al. Neuroprotection by transforming growth factor-beta 1 involves activation of nuclear factor-kappa B through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinasel,2 signaling pathways.Neuriscience.2004; 123:897-906.
29 Zhu M, Feng J, Lucchinetti E,et al.Ischemic postconditioning protects remodeled myocardium via the PDK-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res.2006; 72: 152-162.
30 Zhao JL, Yang YJ, You SJ,et al.Different effects of postconditioning on myocardialno-reflow in the normal and hypercholesterolemic miniswines.Mierovasc Res.2007;73:137-142.
31 Philipp SD,Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A(2b) receptor cascade.Cardiovasc Res.2006;70:308-314.
32 Philipp S,Yang XM,Cui L,et al.Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade.Cardiovasc Res.2006;70:308-314.
33 StaatP, RioufolG, PiotC, et al. Postconditioning the human heart. Circulation.2005; 112: 2143-2148.
34 Ma XJ, Zhang XH,Li CM,et al. Effect of postconditioning on coronary blood flow velocity and endiothelial function and LV recovery after myocardial infarction.J Interven Cardiol.2006; 19:367-375.
1 Murry CE,Jennings RB,Reimer KA,el al.Preconditioning with ischemia:A delay of lethal cell injury in ischemic myocardium.Circulation.1986;74:1124-1136.
2 Zhao ZQ. Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning.Am J Physiol Heart Circ Physiol.2003;285:H579-H 588.
3 Matsubara T, Minatoguchi S.Matsuo H, et al.Three minute.but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease.J Am Coll Cardiol.2000;35:345-351.
4 Mcculy JD,Toyoda Y.Uematsu M,et al. Adenosine enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion.Am J Physiol Heart Circ Physiol.2001;280:H591-H602.
5 Wang G Y,Wu S,Pei JM,et al. Kappa-but not delta-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol.2001; 280:H384-H391.
6 Weinbrenner C, Nelles M, Herzog N,et al.Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction:a newly identified non-neuronal but PKC-dependent pathway.Cardiovasc Res.2002;55:590-601.
7 Kharbanda RK,Mortensen UM,White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo.Circulation.2002;106:2881-2883.
8 Yellon DM,Downey JM.Preconditionin the myocardium:from cellular physiology to clinical cardiology.Physiol Rev.2003;83:1113-1151.
9 Eisen A,Fisman EZ,Rubenfire M,et al.Ischemic preconditioning:nearly two decades of researc: A comprehensive review.Atherosclerosis.2004;172:201-210.
10 Loukogeorgakis SP,Panagiotidou A T,Broadhead MW, et al. Remote ischemic preconditioning provides early and late protection against endothelial ischemia reperfusion injury in humans: role of the autonomic nervous system.J Am Coll Cardiol.2005;46:450-456.
11 Song WY.Dong HL.Cheng Q.et al.Ischemic postconditioning induces neuroprotection via up-regulationof endogenous antioxidant enzyme activities:experiment with rabbits. Zhonghua Yi Xue Za Zhi.2008:88:2355-2359.
12 Zhang YM, Wang Y, Liu XH, et al. Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/reperfusion injury:experiment with rats. Zhonghua Yi Xue Za Zhi.2008;88:2558-2561.
13 Wang KX.Hu SY,Jiang XS,et al.Protective effects of ischaemic postconditioning on warm/cold ischaemic reperfusion injury in rat liver:a comparative study with ischaemic preconditioning.Chin Med J.2008; 121:2004-2009.
14 Somers S,Opie L,Lecour S.Sphingosine-1-phosphate (SIP) can mimic ischaemic postconditioning via activation of the JAK/STAT-3 pathway. Cardiovasc J Afr.2008;19:S33-34.
15 Lacerda L. TNFalpha signalling:a critical role in ischaemic postconditioning?Cardiobasc J Afr.2008;19:S17-18.
16 Ren C,Gao X,Niu G,et al. Delayed postconditioning protects against focal ischemic brain injury in rats.PLOS ONE.2008;3:E3851.
17 Chen Q,Wang Q,Song WY,et al. Effect of sevoflurane postconditioning on spinal cord ischemia reperfusion injury via the release of oxygen free radicals in rabbits. Zhonghua Yi Xue Za Zhi.2008;88:1916-1920.
18 Skyschally A,Van Caster P,Boenqler K,et al. Ischemic Postconditioning in Pigs No Causal Role for Risk Activation.Circ Res.2008;13:115-116.
19 Lemoine S, Beauchef G, Zhu L, et al. Signaling pathways involved in desflurane-induced postconditioning in human atrial myocardium in vitro.Anesthesiology.2008;109:1036-1044.
20 Penna C,Tullio F,Merlina A,et al. Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender. Anesthesiology.2008; 11:120-122.
21 Sinay L,Kvrthy M,Horvath S,et al. Ischaemic postconditioning reduces peroxide formation, cytokine expression and leukocyte activation in reperfusion injury after abdominal aortic surgery in rat model.Clin Hemorheol Microcirc.2008;40:133-142.
22 Oikawa M, Yaoita H, Watanabe K, et al. Attenuation of cardioprotective effect by postconditioning in coronary stenosed rat heart and its restoration by carvedilol.Cira J.2008;72:2081-2086.
23 Sadat U,Varty K. Preconditioning or postconditioning in hepatic surgery. Arch Surg.2008; 143:1026.
24 Pagel PS. Postconditioning by volatile anesthetics:salvaging ischemic myocardium at reperfusion by activation of prosurvival signaling.J Cardiothorac VascAnesth.2008; 22:753-765.
25 Xi L,Das A,Zhao ZQ,et al. Loss of myocardial ischemic postconditioning in adenosine A1 and bradykinin B2 receptors gene knockout mice.Circulation.2008;118:S32-37.
26 Inserte J,Barba I,Hernando V,et al. Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium.Cardiovasc Res.2007;81:116-122.
27 Galagudza M, Kurapeev D, Minasian S,et al.Isehemic postconditioning:brief ischemia during reperfusion converts persistent ventricular fibrillation into regular rhythm..Eur J Cardiothorac Surg.2004;25:1006-1010.
28 Li S,Wu J,Watanabe M,et al. Protective effects of ischemic postconditioning against hypoxia-reoxygenation injury and hydrogen peroxide-induced damage in isolated rat hearts.Exp Clin Cardiol.2006;11:280-285.
29 Goval BK. Microvascular dysfunction and benefit of postconditioning.Catheter Cardiovasc Interv.2008;72:221.
30 Cohen MV,Yang XM,Downey JM. Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning's success.Basic Res Cardiol.2008; 103:461-471.
31 Adams JA,Bassuk JA,Arias J,et al. Acute effects of "delayed postconditioning" with periodic acceleration after asphyxia induced shock in pigs.Pediatr Res.2008;64:533-537.
32 Balakumar P,Rohilla A,Singh M. Preconditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury:what could be the next footstep? Pharmacol
Res.2008;57:403-412.
33 Xing B,Chen H.Zhang M.et al. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat.Stroke.2008;39:2362-2369.
34 Andreadou I,Iliodromitis EK,Koufaki M.et al. Pharmacological pre- and post- conditioning agents:reperfusion-injury of the heart revisited.Mini Rey Med Chem.2008;8:952-959.
35 Sadat U,Walsh SR,Varty K. Cardioprotection by ischemic postconditioning during surgical procedures.Expert Rev Cardiovasc Ther.2008;6:999-1006.
36 Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulation blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation.Basic Res Cardiol.2005; 100:57-63.
37 Lu J,Zang WJ,Yu XJ,et al.Effects of postconditioning of adenosine and acetylcholine on the ischemic isolated rat ventricular myocytes.Eur J Pharmacol.2006;549:133-139.
38 Sun HY,Wang 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.
39 Bopassa jc, Ferrera R,Gateau-Roesch O,el al.PI3-kinase regulates the mitochondrial transition pore in controlled reperfusion andpostconditioning.Cardiovasc Res.2006;69:178-185.
40 Yang XM, Proctor JB,Cui L,et al. Multiple brief coronary occlusion during early reperfusion protect rabbit hearts by targeting cell signal in pathways.J Am Coll cardiol.2004;44:1103-1110.
41 Kin H,Zhao ZQ,SunHY,et al.Postconditioning attenuates myocardial ischemia reperfusion injury by inhibiting events in the early minutes of reperfusion.Cardiovasc Res.2004;62:74-85.
42 Yang XM, Proctor JB, Cui L, et al. Multiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways.J Am Coll Cardiol.2004;44:1103-1110.
43 Darling CE, Jiang R, MaynardM,et al. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts:role of ERK1/2.Am J Physiol Heart Circ Physiol.2005; 289:H1618-1626.
44 Tsang A, Hausenloy DJ, Macanu MM,et al. Postconditioning:A form of "modified reperfusion " protects the myocardium by activating the PI3K-Akt pathway.Circ Res.2004;95:230-232.
45 Manintveld OC.Hekkert M,Bos EJ.et al.Cardiac effects of postconditioning depend critically on the duration of index ischemia.Am J Phy siol Heart Circ Physiol.2006;22:112-113.
46 Tang XL,Sato H,Tiwari S,et al.Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions<45 min.Am J Physiol Heart Cire Physiol.2006;291:H 2308-2317.
47 Kerendi F, Kin H,Halkos ME.et al. Remote postconditioning,brief renal ischemia and reperfusion applied.before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors.Basic Res Cardiol.2005;100:404-412.
48 Fang J,Wu L,Chen L. Postconditioning attenuates cardiocyte ultrastructure injury and apoptosis by blocking mitochondrial permeability transition in rats.Acta Cardiol.2008;63:377-387.
49 Yong QC,Lee SW,Foo CS,et al. Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning. AmJ Physiol Heart Circ Physiol.2008; 295:H1330-H1340.
50 Zhang XH,Li CM,Ma XJ,et al.Correlation of limb and myocardial ischemia postconditioning with acute myocardial reperfusion injury.Zhong hua Yi Xue Za Zhi.2006;86:841-845.
51 范谦,杨新春,王树岩,等.“渐处理”降低了犬心肌缺血／再灌注损伤.Chin J cardi.2006；34：363-366.
52 Zhu M, Feng J,Lucchinetti E,et al.Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res.2006; 72:152-162.
53 ZhaoJL,Yang YJ,You SJ,et al.Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic miniswines.Mierovasc Res.2007;73:137-142.
54 Crisostomo PR,Wang M,Wairiuko GM,et al. Postconditioning in females depends on injury severity.J Surg Res.2006; 134:342-347.
55 彭龙云,马虹,何建桂,等.缺血后处理减轻大鼠肥厚心肌缺血再灌注的观察.中华心血管病杂志.2006；34：685-689.
56 孙胜，高钰琪,高文祥,等.缺氧诱导因子1与PI3K／Akt／mTOR信号转导通路.生命科学.2005；17：311-314.
57 Kin H, Zatta AJ, Lofye MT.et al. Postconditioning reduces infarct size via adenosine receplor activation by endogenous adenosine.Cardiovasc Res.2005;67:124-133.
58 Zhao ZQ,Vinten-Johansen J. Postconditioning:Reduction of reperfusion induced injury.Cardiovasc Res.2006;70:200-211.
59 Krolikowski JG,Weihrauch D,BienengraeberM,et al.Role of Erkl/2 p70s6K,and eNOS in isoflurane-induced cardioprotection during ear reperfusion in vivo.Can J Anaesth. 2006;53:174-282.
60 Pateliya BB, Singh N, Jaggi AS. Possible role of opioids and KATP channels in neuroprotective effect of postconditioning in mice.Biol Pharm Bull.2008;31:1755-1760.
61 Goodman MD,Koch SE,Fuller-Bicer GA,et al. Regulating RISK:a role for JAK-STAT signaling in postconditioning? Am J Physiol Heart Circ Physiol.2008;295:H1649-1656.
62 Boengler K,Hilfiker-Kleiner D,Drexler H,et al. The myocardial JAK/STAT pathway:from protection to failure.Pharmacol Ther.2008;120:172-185.
63 Vessey DA,Li L,Kelley M,et al. Combined sphingosine, SIP and ischemic postconditioning rescue the heart after protracted ischemia.Biochem Biophys Res Commun.2008;375:425-429.
64 Quinlan CL, Costa AD, Costa CL, et al. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels. Am J Physiol Heart Circ Physiol.2008;295:H953-H961.
65 Scartabelli T,Gerace E,Landucci E,et al. Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-Akt signaling pathway:a novel postconditioning strategy?Neuropharmacology.2008;55:509-516.
66 Mykytenko J,Reeves JG,Kin H,et al. Persistent beneficial effect of postconditioning against infarct size:role of mitochondrial K(ATP) channels during reperfusion. Basic Res Cardiol. 2008; 103:472-484.
67 Philipp SD,Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A(2b) receptor cascade.Cardiovasc Res.2006;70:308-314.
68 Philipp S.Yang XM,Cui L.et al.Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade.Cardiovasc Res.2006;70:308-314.
69 Zatta AJ.KinH,Lee G,et al.Infarct-sparing effect of myocardial Posconditioning is dependent on protein kinase C signaling.Cardiova Res.2006;70:315-324.
70 Zatta AJ,Kin H, Lee G, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signaling. Cardiovasc Res.2006;70:315-324.
71 Hausenloy DJ,Tasang A,Yellon DM. The reperfusion injury salvage kinase pathway:a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med.2005; 15:69-75.
72 Zhao ZQ, Sun HY,Wang NP,et al. Hypoxic postconditioning attenuates cardiomyocyte apoptosis via inhibition of jnk and p38 kinases pathway. J Mol Cell Cardiol.2005;38:870.
73 Mykytenko J, Reeves JG, Kin H, et al. Postconditioning reduces infarct size via mitochondrial KATP channel activation during 24 hours of reperfusion J Mol Cell Cardiol.2005;38:830.
74 Yang XM, Proctor JB, Cui L, el al.Multiple,brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways.J Am CollCardiol.2004; 44:1103-1110.
75 Tsang A, Hausenloy DJ,Mocanu MM,et al.Postconditioning:A form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase akt pathway. Circ Res.2004;95:230-232.
76 Argaud L, Gateau-Roesch O, Raiskey O,et al. Postconditioning inhibits mitochondrial permeability transition.Circulation.2005; 111:194-197.
77 Wang HC,Zhang HF, Guo WY,et al.Hypoxic postconditioning enhances the survival and inhibits apoptosis of cardiomyocytes following reoxygenation:role of Peroxynitrite formation.Apoptos.is.2006;11:1453-1460.
78 Wang J,Gao Q,Shen J,et al. Kappa-opioid receptor mediates the cardioprotective effect of ischemic postconditioning.Zhejiang Da Xue Xue Bao Yi Xue Ban.2007;36:41-47.
79 Fujita M.Asanuma H.Hirata A.et al.Prolonged Transient Acidosis During Early Reperfusion Contributes to the Cardioprotective Effects of Postconditioning.Am J Physiol Heart Cire Physlol.2007;5:123-125.
80 Sun HY.Wang NP.Kerendi F,et al.Hypoxic Postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+overload.Am J Physiol Heart Circ Physiol.2005;288:1900-1908.
81 Staat P.Riofol G.Plot C,et al. Postconditioning the human heart.Circulation.2005; 112:2143-2148.
82 Zhao ZQ.Corvera JS,HalkosME,et al.Inhibition of myocardial injury by ischemic Postconditioning during reperfusion.comparision with ischemic preconditioning.Am J Physiol. 2003;285:579-588.
83 HalkosME.Kerendi F,Corvera JS.et al.Myocardial protection with Postconditioning is not enhanced by ischemic preconditioning.AnnThorac Surg.2004;78:961-969.
84 Dosenko VE,Nagibin VS.Tumanovskaya LV,et al.Postconditioningprevents apoptotic necrotic and autophagic cardiomyocyte cell death in culture.Fiziol Zh.2005;51:12-17.
85 Argaud L, Gateau O, Raisky O,et al. Postconditioning inhibit mitochondrial permeability transition.Circulation.2005;111:194-197.
86 Yellon DM, Hausenloy DJ.Realizing the clinical potential of ischemic preconditioning and Postconditioning.Nat Clin Pract Cardiovasc Med.2005;2:568-575.
87 Iliodromitis EK, Zoga A,Vrettou A, et al.The effectiveness of Postconitioning and preconditioningon infarct size in hypercholesterolemic and normal anesthetized rabbits Am J Physiol.2008;28:79-88.
.88 Chen HT,Yang CX,Li H,et al. Cardioprotection of sevoflurane postconditioning by activating extracellular signal-regulated kinase 1/2 in isolated rat hearts.Acta Pharmacol Sin.2008;29: 931-941.
89 Laskey WK. Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction:a pilot study.Catheter Cardiovasc. Interv.2005;65:361-367.
90 StaatP.RioufolG,PiotC,et al. Postconditioning the human heart.Circulation.2005;112:2143-2148.
91 Ma XJ, Zhang XH.Li CM,et al. Effect of postconditioning on coronary blood flow velocity and endiothelial function and LV recovery after myocardial infarction.J Interven Cardiol.2006; 19:367-375.
92 Lim S Y. Bae EH. Jeong MH, et al. Effect of combined intracoronary adenosine and nicorandil on no-reflow phenomenon during percutaneous coronary intervention.Circ J.2004;68:928-932.
93 史斌,陈玉培.尼可地尔后处理对大鼠心肌缺血再灌注损伤的影响.中华麻醉学杂志.2007；27：309-311.
94刘军,夏勇.李东野.等.阿托伐他汀早期干预对急性心肌梗死心肌细胞凋亡的影响.中国心血管病研究杂志.2007；5：292-294.
95 Krolikowski JG, Bienengraeber M. Weihrauch D,et al. Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion:the role mitochondrial KATP channels. Anesth Analg.2005; 101:1590-1596.
96 Pagel PS,Krolikowski JG,Neff DA,et al.Inhibition of glycogen synthase kinase enhances isoflurance-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg.2006;102:1348-1354.
97 Crisostomo PR,Wang M,Wairiuko GM,et al.Postcondifioning in females depends on injury severity.J Surg Res.2006; 134:342-347.
98 Tissier R,Waintraub X,CouvreurN,et al. Pharmacological postconditioning with the phytoestrogen genistein.J Mol Cell Cadiol.2007; 42:79-87.
99 Zhang XH,Li CM,Ma XJ,et al.Physiologically tolerable insulin reducesvmyocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs.J Cardiovasc Phmmacol.2006;48:306-313.
100 Onimaru S, Nakamura K, Kariyazono H, et al. Inhibitory effects of edaravone on the production of tumor necrosis factor-a in the isolated heart undergoing ischemia and reperfusion. Heart Vessels.2006; 21:108-115.
101 Zhao JL, Yang YJ, Cui CJ, et al. Different effects of adenosine and calcium channel blockade on myocardial no-reflow after acute myocardial infarction and reperfusion. Cardiovasc Drugs Ther.2006:20:167-175.
2 Zhao ZQ. Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning.Am J Physiol Heart Circ Physiol.2003;285:H579-H 588.
3 Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulation blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation.Basic Res Cardiol.2005;100:57-63.
4 ZhaoJL, Yang YJ, You SJ, et al.Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic miniswines.Mierovasc Res.2007;73:137-142.
5 Scartabelli T,Gerace E,Landucci E,et al. Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-Akt signaling pathway:a novel postconditioning strategy?.Neuropharmacology.2008;55:509-516.
6 李立明,饶克勤,孔灵芝,等.中国居民营养与健康状况调查技术执行组.中国居民2002年营养与健康状况调查.中华流行病学杂志.2005；26：478-484.
7 American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes care.2007; 30:S42-47.
8 《中国糖尿病防治指南》编写组.中国糖尿病防治指南.北京大学医学出版社,2008.
9 Larosa JC,Grundy,Water DD, et al. Treating to New Targets (TNT) Investigators.Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med.2005; 352:1425-1435.
10 Van Domburg RT, Sonnenschein K, Nieuwlaat R, et al. Sustained benefit 20 years after reperfusion therapy in acute therapy in acute myocardial infarction.J Am Coll Cardiol. 2005;46:15-20.
11 Song WY,Dong HL,Cheng Q,et al.Ischemic postconditioning induces neuroprotection
via up-regulationof endogenous antioxidant enzyme activities experiment with rabbits. Zhonghua Yi Xue Za Zhi.2008,88:2355-2359.
12 Zhang YM, Wang Y, Liu XH. et al. Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/reperfusion injury:experiment with rat. Zhonghua Yi Xue Za Zhi.2008:88:2558-2561.
13 Wang KX,Hu SY,Jiang XS, et al.Protective effects of ischaemic postconditioning on warm/cold ischaemic reperfusion injury in rat liver:a comparative study with ischaemic preconditioning.Chin Med J.2008;121:2004-2009.
14 Somers S, Opie L, Lecour S. Sphingosine-1-phosphate (SIP) can mimic ischaemic postconditioning via activation of the JAK/STAT-3 pathway. Cardiovasc J Afr.2008;19: S33-34.
15 Lacerda L. TNF alpha signalling:a critical role in ischaemic postconditioning? Cardiobasc J Afr.2008;19:S17-18.
16 Yang XM, Proctor JB,Cui L,et al. Multiple brief coronary occlusion during early reperfusion protect rabbit hearts by targeting cell signal in pathways.J Am Coll cardiol.2004;44:1103-1110.
17 Kin H, Zhao ZQ, SunHY,et al. Postconditioning attenuates myocardial ischemia reperfusion injury by inhibiting events in the early minutes of reperfusion.Cardiovasc Res.2004; 62:74-85.
18 Yang XM, Proctor JB, Cui L, et al. Multiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways J Am Coll Cardiol.2004; 44:1103-1110.
19 Ravingerova T, Stetka R, Paneza D,et al. Susceptibility to isehemia-indueed arrhythmias and the effete of preeonditioning in the diabetic rat heart. Physiol Res.2000; 49:607-616.
20 Gross ER, Gross GJ. Ligand triggers of classical preconditioning and postconditioning. Cardiovasc Res.2006;70:212-221.
21 Mocanu MM, Baxter GF,Yellon DM.Caspase inhibition and limitation of myocardial infarct size:protection against lethal reperfusioninjury.Br J Pharmacol.2000; 130:197-200.
22 Zhao ZQ. Morris CD, Budde JM. et al.Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion. Cardiovasc Res 2003;59:132-142.
23 Argaud L, Gateau-Roesch, O, Raisky O, et al. Post-conditioning inhibits mitochondrial permeability transition.Circulation.2005; 111:194-197.
24 Tsang A, Hausenloy DJ, Macanu MM, et al. Postconditioning:A form of "modified reperfusion " protects the myocardium by activating the PI3K-Akt pathway[J].Circ Res.2004; 95:230-232.
25 Bopassa jc, Ferrera R,Gateau-Roesch O,el al.PI3-kinase regulates the mitochondrial transition pore in controlled reperfusion andpostconditioning.Cardiovasc Res.2006;69:178-185.
26 Won CK, Ha SJ, Noh HS, et al.Estradiol prevents the injury induced decrease of Akt activation and Bad phosphorylation. Neurosci lett.2005; 387:115-119.
27 Hwang IK.Yoo KY.Park SK, et al. Expression and changes of endogenous insulin-like growth factor-1 in neurons and gila in the gerbil hippocampus and dentate gyros after ischemic insult.Neuro-chem Int.2004;45:149-156.
28 Zhu Y, Culmsee C, Klumpp S, et al. Neuroprotection by transforming growth factor-beta 1 involves activation of nuclear factor-kappa B through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinasel,2 signaling pathways.Neuriscience.2004; 123:897-906.
29 Zhu M, Feng J, Lucchinetti E,et al.Ischemic postconditioning protects remodeled myocardium via the PDK-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res.2006; 72: 152-162.
30 Zhao JL, Yang YJ, You SJ,et al.Different effects of postconditioning on myocardialno-reflow in the normal and hypercholesterolemic miniswines.Mierovasc Res.2007;73:137-142.
31 Philipp SD,Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A(2b) receptor cascade.Cardiovasc Res.2006;70:308-314.
32 Philipp S,Yang XM,Cui L,et al.Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade.Cardiovasc Res.2006;70:308-314.
33 StaatP, RioufolG, PiotC, et al. Postconditioning the human heart. Circulation.2005; 112: 2143-2148.
34 Ma XJ, Zhang XH,Li CM,et al. Effect of postconditioning on coronary blood flow velocity and endiothelial function and LV recovery after myocardial infarction.J Interven Cardiol.2006; 19:367-375.
1 Murry CE,Jennings RB,Reimer KA,el al.Preconditioning with ischemia:A delay of lethal cell injury in ischemic myocardium.Circulation.1986;74:1124-1136.
2 Zhao ZQ. Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning.Am J Physiol Heart Circ Physiol.2003;285:H579-H 588.
3 Matsubara T, Minatoguchi S.Matsuo H, et al.Three minute.but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease.J Am Coll Cardiol.2000;35:345-351.
4 Mcculy JD,Toyoda Y.Uematsu M,et al. Adenosine enhanced ischemic preconditioning: adenosine receptor involvement during ischemia and reperfusion.Am J Physiol Heart Circ Physiol.2001;280:H591-H602.
5 Wang G Y,Wu S,Pei JM,et al. Kappa-but not delta-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol.2001; 280:H384-H391.
6 Weinbrenner C, Nelles M, Herzog N,et al.Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction:a newly identified non-neuronal but PKC-dependent pathway.Cardiovasc Res.2002;55:590-601.
7 Kharbanda RK,Mortensen UM,White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo.Circulation.2002;106:2881-2883.
8 Yellon DM,Downey JM.Preconditionin the myocardium:from cellular physiology to clinical cardiology.Physiol Rev.2003;83:1113-1151.
9 Eisen A,Fisman EZ,Rubenfire M,et al.Ischemic preconditioning:nearly two decades of researc: A comprehensive review.Atherosclerosis.2004;172:201-210.
10 Loukogeorgakis SP,Panagiotidou A T,Broadhead MW, et al. Remote ischemic preconditioning provides early and late protection against endothelial ischemia reperfusion injury in humans: role of the autonomic nervous system.J Am Coll Cardiol.2005;46:450-456.
11 Song WY.Dong HL.Cheng Q.et al.Ischemic postconditioning induces neuroprotection via up-regulationof endogenous antioxidant enzyme activities:experiment with rabbits. Zhonghua Yi Xue Za Zhi.2008:88:2355-2359.
12 Zhang YM, Wang Y, Liu XH, et al. Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/reperfusion injury:experiment with rats. Zhonghua Yi Xue Za Zhi.2008;88:2558-2561.
13 Wang KX.Hu SY,Jiang XS,et al.Protective effects of ischaemic postconditioning on warm/cold ischaemic reperfusion injury in rat liver:a comparative study with ischaemic preconditioning.Chin Med J.2008; 121:2004-2009.
14 Somers S,Opie L,Lecour S.Sphingosine-1-phosphate (SIP) can mimic ischaemic postconditioning via activation of the JAK/STAT-3 pathway. Cardiovasc J Afr.2008;19:S33-34.
15 Lacerda L. TNFalpha signalling:a critical role in ischaemic postconditioning?Cardiobasc J Afr.2008;19:S17-18.
16 Ren C,Gao X,Niu G,et al. Delayed postconditioning protects against focal ischemic brain injury in rats.PLOS ONE.2008;3:E3851.
17 Chen Q,Wang Q,Song WY,et al. Effect of sevoflurane postconditioning on spinal cord ischemia reperfusion injury via the release of oxygen free radicals in rabbits. Zhonghua Yi Xue Za Zhi.2008;88:1916-1920.
18 Skyschally A,Van Caster P,Boenqler K,et al. Ischemic Postconditioning in Pigs No Causal Role for Risk Activation.Circ Res.2008;13:115-116.
19 Lemoine S, Beauchef G, Zhu L, et al. Signaling pathways involved in desflurane-induced postconditioning in human atrial myocardium in vitro.Anesthesiology.2008;109:1036-1044.
20 Penna C,Tullio F,Merlina A,et al. Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender. Anesthesiology.2008; 11:120-122.
21 Sinay L,Kvrthy M,Horvath S,et al. Ischaemic postconditioning reduces peroxide formation, cytokine expression and leukocyte activation in reperfusion injury after abdominal aortic surgery in rat model.Clin Hemorheol Microcirc.2008;40:133-142.
22 Oikawa M, Yaoita H, Watanabe K, et al. Attenuation of cardioprotective effect by postconditioning in coronary stenosed rat heart and its restoration by carvedilol.Cira J.2008;72:2081-2086.
23 Sadat U,Varty K. Preconditioning or postconditioning in hepatic surgery. Arch Surg.2008; 143:1026.
24 Pagel PS. Postconditioning by volatile anesthetics:salvaging ischemic myocardium at reperfusion by activation of prosurvival signaling.J Cardiothorac VascAnesth.2008; 22:753-765.
25 Xi L,Das A,Zhao ZQ,et al. Loss of myocardial ischemic postconditioning in adenosine A1 and bradykinin B2 receptors gene knockout mice.Circulation.2008;118:S32-37.
26 Inserte J,Barba I,Hernando V,et al. Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium.Cardiovasc Res.2007;81:116-122.
27 Galagudza M, Kurapeev D, Minasian S,et al.Isehemic postconditioning:brief ischemia during reperfusion converts persistent ventricular fibrillation into regular rhythm..Eur J Cardiothorac Surg.2004;25:1006-1010.
28 Li S,Wu J,Watanabe M,et al. Protective effects of ischemic postconditioning against hypoxia-reoxygenation injury and hydrogen peroxide-induced damage in isolated rat hearts.Exp Clin Cardiol.2006;11:280-285.
29 Goval BK. Microvascular dysfunction and benefit of postconditioning.Catheter Cardiovasc Interv.2008;72:221.
30 Cohen MV,Yang XM,Downey JM. Acidosis, oxygen, and interference with mitochondrial permeability transition pore formation in the early minutes of reperfusion are critical to postconditioning's success.Basic Res Cardiol.2008; 103:461-471.
31 Adams JA,Bassuk JA,Arias J,et al. Acute effects of "delayed postconditioning" with periodic acceleration after asphyxia induced shock in pigs.Pediatr Res.2008;64:533-537.
32 Balakumar P,Rohilla A,Singh M. Preconditioning and postconditioning to limit ischemia-reperfusion-induced myocardial injury:what could be the next footstep? Pharmacol
Res.2008;57:403-412.
33 Xing B,Chen H.Zhang M.et al. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat.Stroke.2008;39:2362-2369.
34 Andreadou I,Iliodromitis EK,Koufaki M.et al. Pharmacological pre- and post- conditioning agents:reperfusion-injury of the heart revisited.Mini Rey Med Chem.2008;8:952-959.
35 Sadat U,Walsh SR,Varty K. Cardioprotection by ischemic postconditioning during surgical procedures.Expert Rev Cardiovasc Ther.2008;6:999-1006.
36 Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulation blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylate cyclase activation.Basic Res Cardiol.2005; 100:57-63.
37 Lu J,Zang WJ,Yu XJ,et al.Effects of postconditioning of adenosine and acetylcholine on the ischemic isolated rat ventricular myocytes.Eur J Pharmacol.2006;549:133-139.
38 Sun HY,Wang 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.
39 Bopassa jc, Ferrera R,Gateau-Roesch O,el al.PI3-kinase regulates the mitochondrial transition pore in controlled reperfusion andpostconditioning.Cardiovasc Res.2006;69:178-185.
40 Yang XM, Proctor JB,Cui L,et al. Multiple brief coronary occlusion during early reperfusion protect rabbit hearts by targeting cell signal in pathways.J Am Coll cardiol.2004;44:1103-1110.
41 Kin H,Zhao ZQ,SunHY,et al.Postconditioning attenuates myocardial ischemia reperfusion injury by inhibiting events in the early minutes of reperfusion.Cardiovasc Res.2004;62:74-85.
42 Yang XM, Proctor JB, Cui L, et al. Multiple brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways.J Am Coll Cardiol.2004;44:1103-1110.
43 Darling CE, Jiang R, MaynardM,et al. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts:role of ERK1/2.Am J Physiol Heart Circ Physiol.2005; 289:H1618-1626.
44 Tsang A, Hausenloy DJ, Macanu MM,et al. Postconditioning:A form of "modified reperfusion " protects the myocardium by activating the PI3K-Akt pathway.Circ Res.2004;95:230-232.
45 Manintveld OC.Hekkert M,Bos EJ.et al.Cardiac effects of postconditioning depend critically on the duration of index ischemia.Am J Phy siol Heart Circ Physiol.2006;22:112-113.
46 Tang XL,Sato H,Tiwari S,et al.Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions<45 min.Am J Physiol Heart Cire Physiol.2006;291:H 2308-2317.
47 Kerendi F, Kin H,Halkos ME.et al. Remote postconditioning,brief renal ischemia and reperfusion applied.before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors.Basic Res Cardiol.2005;100:404-412.
48 Fang J,Wu L,Chen L. Postconditioning attenuates cardiocyte ultrastructure injury and apoptosis by blocking mitochondrial permeability transition in rats.Acta Cardiol.2008;63:377-387.
49 Yong QC,Lee SW,Foo CS,et al. Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning. AmJ Physiol Heart Circ Physiol.2008; 295:H1330-H1340.
50 Zhang XH,Li CM,Ma XJ,et al.Correlation of limb and myocardial ischemia postconditioning with acute myocardial reperfusion injury.Zhong hua Yi Xue Za Zhi.2006;86:841-845.
51 范谦,杨新春,王树岩,等.“渐处理”降低了犬心肌缺血／再灌注损伤.Chin J cardi.2006；34：363-366.
52 Zhu M, Feng J,Lucchinetti E,et al.Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res.2006; 72:152-162.
53 ZhaoJL,Yang YJ,You SJ,et al.Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic miniswines.Mierovasc Res.2007;73:137-142.
54 Crisostomo PR,Wang M,Wairiuko GM,et al. Postconditioning in females depends on injury severity.J Surg Res.2006; 134:342-347.
55 彭龙云,马虹,何建桂,等.缺血后处理减轻大鼠肥厚心肌缺血再灌注的观察.中华心血管病杂志.2006；34：685-689.
56 孙胜，高钰琪,高文祥,等.缺氧诱导因子1与PI3K／Akt／mTOR信号转导通路.生命科学.2005；17：311-314.
57 Kin H, Zatta AJ, Lofye MT.et al. Postconditioning reduces infarct size via adenosine receplor activation by endogenous adenosine.Cardiovasc Res.2005;67:124-133.
58 Zhao ZQ,Vinten-Johansen J. Postconditioning:Reduction of reperfusion induced injury.Cardiovasc Res.2006;70:200-211.
59 Krolikowski JG,Weihrauch D,BienengraeberM,et al.Role of Erkl/2 p70s6K,and eNOS in isoflurane-induced cardioprotection during ear reperfusion in vivo.Can J Anaesth. 2006;53:174-282.
60 Pateliya BB, Singh N, Jaggi AS. Possible role of opioids and KATP channels in neuroprotective effect of postconditioning in mice.Biol Pharm Bull.2008;31:1755-1760.
61 Goodman MD,Koch SE,Fuller-Bicer GA,et al. Regulating RISK:a role for JAK-STAT signaling in postconditioning? Am J Physiol Heart Circ Physiol.2008;295:H1649-1656.
62 Boengler K,Hilfiker-Kleiner D,Drexler H,et al. The myocardial JAK/STAT pathway:from protection to failure.Pharmacol Ther.2008;120:172-185.
63 Vessey DA,Li L,Kelley M,et al. Combined sphingosine, SIP and ischemic postconditioning rescue the heart after protracted ischemia.Biochem Biophys Res Commun.2008;375:425-429.
64 Quinlan CL, Costa AD, Costa CL, et al. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels. Am J Physiol Heart Circ Physiol.2008;295:H953-H961.
65 Scartabelli T,Gerace E,Landucci E,et al. Neuroprotection by group I mGlu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the PI3K-Akt signaling pathway:a novel postconditioning strategy?Neuropharmacology.2008;55:509-516.
66 Mykytenko J,Reeves JG,Kin H,et al. Persistent beneficial effect of postconditioning against infarct size:role of mitochondrial K(ATP) channels during reperfusion. Basic Res Cardiol. 2008; 103:472-484.
67 Philipp SD,Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A(2b) receptor cascade.Cardiovasc Res.2006;70:308-314.
68 Philipp S.Yang XM,Cui L.et al.Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade.Cardiovasc Res.2006;70:308-314.
69 Zatta AJ.KinH,Lee G,et al.Infarct-sparing effect of myocardial Posconditioning is dependent on protein kinase C signaling.Cardiova Res.2006;70:315-324.
70 Zatta AJ,Kin H, Lee G, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signaling. Cardiovasc Res.2006;70:315-324.
71 Hausenloy DJ,Tasang A,Yellon DM. The reperfusion injury salvage kinase pathway:a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med.2005; 15:69-75.
72 Zhao ZQ, Sun HY,Wang NP,et al. Hypoxic postconditioning attenuates cardiomyocyte apoptosis via inhibition of jnk and p38 kinases pathway. J Mol Cell Cardiol.2005;38:870.
73 Mykytenko J, Reeves JG, Kin H, et al. Postconditioning reduces infarct size via mitochondrial KATP channel activation during 24 hours of reperfusion J Mol Cell Cardiol.2005;38:830.
74 Yang XM, Proctor JB, Cui L, el al.Multiple,brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways.J Am CollCardiol.2004; 44:1103-1110.
75 Tsang A, Hausenloy DJ,Mocanu MM,et al.Postconditioning:A form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase akt pathway. Circ Res.2004;95:230-232.
76 Argaud L, Gateau-Roesch O, Raiskey O,et al. Postconditioning inhibits mitochondrial permeability transition.Circulation.2005; 111:194-197.
77 Wang HC,Zhang HF, Guo WY,et al.Hypoxic postconditioning enhances the survival and inhibits apoptosis of cardiomyocytes following reoxygenation:role of Peroxynitrite formation.Apoptos.is.2006;11:1453-1460.
78 Wang J,Gao Q,Shen J,et al. Kappa-opioid receptor mediates the cardioprotective effect of ischemic postconditioning.Zhejiang Da Xue Xue Bao Yi Xue Ban.2007;36:41-47.
79 Fujita M.Asanuma H.Hirata A.et al.Prolonged Transient Acidosis During Early Reperfusion Contributes to the Cardioprotective Effects of Postconditioning.Am J Physiol Heart Cire Physlol.2007;5:123-125.
80 Sun HY.Wang NP.Kerendi F,et al.Hypoxic Postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+overload.Am J Physiol Heart Circ Physiol.2005;288:1900-1908.
81 Staat P.Riofol G.Plot C,et al. Postconditioning the human heart.Circulation.2005; 112:2143-2148.
82 Zhao ZQ.Corvera JS,HalkosME,et al.Inhibition of myocardial injury by ischemic Postconditioning during reperfusion.comparision with ischemic preconditioning.Am J Physiol. 2003;285:579-588.
83 HalkosME.Kerendi F,Corvera JS.et al.Myocardial protection with Postconditioning is not enhanced by ischemic preconditioning.AnnThorac Surg.2004;78:961-969.
84 Dosenko VE,Nagibin VS.Tumanovskaya LV,et al.Postconditioningprevents apoptotic necrotic and autophagic cardiomyocyte cell death in culture.Fiziol Zh.2005;51:12-17.
85 Argaud L, Gateau O, Raisky O,et al. Postconditioning inhibit mitochondrial permeability transition.Circulation.2005;111:194-197.
86 Yellon DM, Hausenloy DJ.Realizing the clinical potential of ischemic preconditioning and Postconditioning.Nat Clin Pract Cardiovasc Med.2005;2:568-575.
87 Iliodromitis EK, Zoga A,Vrettou A, et al.The effectiveness of Postconitioning and preconditioningon infarct size in hypercholesterolemic and normal anesthetized rabbits Am J Physiol.2008;28:79-88.
.88 Chen HT,Yang CX,Li H,et al. Cardioprotection of sevoflurane postconditioning by activating extracellular signal-regulated kinase 1/2 in isolated rat hearts.Acta Pharmacol Sin.2008;29: 931-941.
89 Laskey WK. Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction:a pilot study.Catheter Cardiovasc. Interv.2005;65:361-367.
90 StaatP.RioufolG,PiotC,et al. Postconditioning the human heart.Circulation.2005;112:2143-2148.
91 Ma XJ, Zhang XH.Li CM,et al. Effect of postconditioning on coronary blood flow velocity and endiothelial function and LV recovery after myocardial infarction.J Interven Cardiol.2006; 19:367-375.
92 Lim S Y. Bae EH. Jeong MH, et al. Effect of combined intracoronary adenosine and nicorandil on no-reflow phenomenon during percutaneous coronary intervention.Circ J.2004;68:928-932.
93 史斌,陈玉培.尼可地尔后处理对大鼠心肌缺血再灌注损伤的影响.中华麻醉学杂志.2007；27：309-311.
94刘军,夏勇.李东野.等.阿托伐他汀早期干预对急性心肌梗死心肌细胞凋亡的影响.中国心血管病研究杂志.2007；5：292-294.
95 Krolikowski JG, Bienengraeber M. Weihrauch D,et al. Inhibition of mitochondrial permeability transition enhances isoflurane-induced cardioprotection during early reperfusion:the role mitochondrial KATP channels. Anesth Analg.2005; 101:1590-1596.
96 Pagel PS,Krolikowski JG,Neff DA,et al.Inhibition of glycogen synthase kinase enhances isoflurance-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg.2006;102:1348-1354.
97 Crisostomo PR,Wang M,Wairiuko GM,et al.Postcondifioning in females depends on injury severity.J Surg Res.2006; 134:342-347.
98 Tissier R,Waintraub X,CouvreurN,et al. Pharmacological postconditioning with the phytoestrogen genistein.J Mol Cell Cadiol.2007; 42:79-87.
99 Zhang XH,Li CM,Ma XJ,et al.Physiologically tolerable insulin reducesvmyocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs.J Cardiovasc Phmmacol.2006;48:306-313.
100 Onimaru S, Nakamura K, Kariyazono H, et al. Inhibitory effects of edaravone on the production of tumor necrosis factor-a in the isolated heart undergoing ischemia and reperfusion. Heart Vessels.2006; 21:108-115.
101 Zhao JL, Yang YJ, Cui CJ, et al. Different effects of adenosine and calcium channel blockade on myocardial no-reflow after acute myocardial infarction and reperfusion. Cardiovasc Drugs Ther.2006:20:167-175.