大鼠心肌缺血后适应和改良方案中p38/JNK MAPK信号通路变化及其对心肌缺血再灌注损伤的影响
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摘要
第一部分机械后适应中磷酸化p38／JNK变化及其对心肌再灌注损伤的影响
目的探讨大鼠心肌缺血后适应中磷酸化p38/JNK MAPK的变化,并进一步分析其与心肌再灌注损伤的关系。方法70只雄性大鼠随机分为假手术组、缺血再灌注组(R／I)、机械后适应组(Post)、JNK抑制剂SP600125组(SP)、p38抑制剂SB203580组(SB)、p38／JNK激活剂Anisomycin+后适应组(Ani+Post)和p38／JNK激活剂Anisomycin (Ani)组七组。建立急性心肌梗死再灌注模型,根据分组在缺血结束前5min经颈静脉持续注射相应药物,缺血结束时注射完毕。在不同时间点处死大鼠分别测定心肌凋亡、坏死、梗死面积和凋亡途径分子的表达。结果SP和SB组较R／I组血流动力学指标显著改善,细胞凋亡和坏死减轻,心肌梗死面积减少,同时伴随凋亡信号分子降低(P<0.05)；SP和SB组同Post组相比上述指标均无明显差异。SP组P-JNK显著低于R／I组(P<0.05),同Post组相似(P>0.05)；SB组P-p38显著低于R／I组(P<0.05),同Post组相似(P>0.05)。Ani+Post组部分抵消了Post组的心肌保护效应,Post组各指标均显著优于Ani+Post组(P<0.05)；Ani组各项指标均与R／I组相似(P>0.05)。结论机械后适应可以抑制p38/JNK MAPK在心肌再灌注损伤中的磷酸化,并通过P-p38和P-JNK的减少抑制了细胞死亡受体途径和线粒体途径凋亡的发生。
第二部分机械后适应改良方案-渐进延长再灌注模式减轻心肌缺血再灌注损伤及其机制的研究
目的探讨后适应不同模式对大鼠急性心肌缺血再灌注损伤的影响并进一步研究其机制。方法60只雄性大鼠随机分为假手术组、缺血再灌注组(R／I)、后适应渐进缩短再灌注组(GDR)、后适应相等再灌注组(ER)和后适应渐进延长再灌注组(GIR)五组。建立急性心肌梗死再灌注和缺血后适应模型,根据分组给予不同后适应处理,在不同时间点处死大鼠分别测定心肌凋亡、坏死、梗死面积和凋亡途径分子的表达。结果三种后适应处理组较R／I组均可显著改善血流动力学指标、减轻细胞凋亡和坏死、限制心肌梗死面积；同时伴随P-p38,P-JNK等致凋亡分子表达显著减少(P<0.05)。上述变化GIR组最为明显,其次是ER组,GDR组最不显著。GIR组同ER组相比,除心肌梗死面积减轻未达显著性差异外(P>0.05),上述指标均明显优于ER组(P<0.05)。以上指标GIR组均显著优于GDR组(P<0.05)。结论后适应渐进延长再灌注模式能发挥更大程度的心肌保护作用,这可能与其更大程度激活ERK、抑制p38／JNK活化、抑制细胞死亡受体和线粒体凋亡途径相关。
第三部分乳酸和低剂量依达拉奉联合药物后适应减轻心肌缺血再灌注损伤及其机制的研究
目的探讨乳酸和低剂量氧自由基清除剂依达拉奉能否模拟后适应发挥有效的心肌保护作用并进一步研究其机制。方法108只雄性大鼠随机分为假手术组、缺血再灌注组(R／I)、后适应组(Post)、乳酸组(Lac)、低剂量依达拉奉组(Eda)、乳酸+低剂量依达拉奉组(Lac+Eda)六组。建立急性心肌梗死再灌注模型,在再灌注即刻使用微量注射器根据不同组别,在梗死边缘注射不同药物或生理盐水。测定再灌注10min后右心房血浆pH值,在不同时间点处死大鼠分别测定心肌凋亡、坏死、梗死面积和凋亡途径分子的表达。结果Lac和Lac+Eda组右心房血浆pH值较Post组相似(P>0.05)；Lac+Eda组再灌注1h和6h后线粒体吸光度较Post组相似(P>0.05),而Lac组在再灌注6h后期线粒体吸光度显著低于Post组(P<0.05)。Eda和Lac+Eda组MDA和SOD含量均与Post组相似(P>0.05)。Lac+Eda组较R／I组可显著改善血流动力学,减轻细胞凋亡和坏死,限制心肌梗死面积,同时伴随各凋亡途径分子表达显著减少(P<0.05)；且同Post组相比上述指标均无明显差异(P>0.05)。Lac和Eda组在上述指标方面较R／I组部分改善,但同Post组相比仍有明显差异(P<0.05)。结论局部注射乳酸能较好模拟后适应带来的酸中毒延长,局部注射低剂量依达拉奉能较好模拟后适应开始时合成的适量氧自由基；乳酸和低剂量依达拉奉联合使用可较好模拟后适应上游触发因子,有效减轻再灌注损伤。
Part One:The Change of Phospho-p38/JNK and Its Influence on Myocardial Reperfusion Injury in Mechanical Postconditioning
Objective:Study the change of Phospho-p38/JNK MAPK and its influence on myocardial reperfusion injury in mechanical postconditioning. Methods:70 rats were randomly divided into 7 groups:sham, reperfusion/injury(R/I), postconditioning (Post), SP600125 (SP), SB203580 (SB), Anisomycin+Post (Ani+Post) and Anisomycin (Ani). Results:Compared with R/I group, the level of serum marker, apoptotic index, infarct size, the expression of molecules leading to apoptosis in SP and SB group were all significantly lower (P< 0.05). The expression of P-JNK in SP group was lower than R/I group (P<0.05) and similar with Post group (P>0.05). The expression of P-p38 in SB group was lower than R/I group (P<0.05) and similar with Post group (P>0.05). On the other hand Ani+Post group lost cardioprotection partly, all variables in Ani group were similar with those in R/I group (P>0.05). Conclusion:Postconditioning could inhibit phosphorylation of p38/JNK MAPK, through which it attenuates cardiomyocyte apoptosis by both death receptor and mitochondria pathway.
Part Two:Improved Algorithm-Gradual Increased Reperfusion in Postconditioning Plays Better Role in Cardioprotection
Objective:Study cardioprotection of different postconditioning algorithm, and investigate the mechanism in the process. Methods:60 rats were randomly divided into 5 groups:sham, reperfusion/injury(R/I), postconditioning (Post), gradual decreased reperfusion (GDR), equal reperfusion(ER), and gradual increased reperfusion (GIR). Results:Compared with R/I group, the level of homodynamic variables, serum marker of myocardium, apoptotic index, infarct size, the expression molecules leading to apoptosis in GDR, ER and GIR group were lower significantly (P<0.05). The difference of GIR was the most, and then was ER and the last was GDR group. Compared with ER group, except for infarct size was similar (P>0.05), variables in GDR group were all much better (P <0.05). Conclusion:Gradual increased reperfusion algorithm of postconditioning could relieve reperfusion injury more significantly, this is probably because it could activate ERK and inhibit p38/JNK MAPK more seriously.
Part Three:Pharmacological Postconditioning with Lactic Acid and Low Dose of Edaravone could Attenuate Myocardial Reperfusion Injury
Objective:The aim of this study was to test the hypothesis that pharmacological postconditioning with lactic acid and low dose of edaravone could mimic the upper trigger of mechanical postconditioning and relieve reperfusion injury. Methods:108 rats were randomly divided into 6 groups:sham, reperfusion/injury(R/I), postconditioning (Post), lactic acid (Lac), low dose of edaravone (Eda), and lactic acid+low dose of edaravone edaravone (Lac+Eda).
Results:Compared with Post group, pH of blood from right atrium in Lac and Lac+Eda group were similar (P>0.05); and the level of MDA and SOD in Eda and Lac+Eda group were also similar (P>0.05). The level of homodynamic variables, serum marker of myocardium, apoptotic index, infarct size, the expression molecules leading to apoptosis in Lac+Eda group were all similar with Post group(P>0.05). Lac and Eda group could mimic the cardioprotection partly.
Conclusion:Lactic acid injected in ischemic myocardium at the onset of reperfusion could mimic the prolonged local acidosis in postconditioning, and pharmacological postconditioning with lactic acid and low dose of edaravone could mimic the upper trigger of mechanical postconditioning and attenuate myocardial reperfusion injury.
目的探讨大鼠心肌缺血后适应中磷酸化p38/JNK MAPK的变化,并进一步分析其与心肌再灌注损伤的关系。方法70只雄性大鼠随机分为假手术组、缺血再灌注组(R／I)、机械后适应组(Post)、JNK抑制剂SP600125组(SP)、p38抑制剂SB203580组(SB)、p38／JNK激活剂Anisomycin+后适应组(Ani+Post)和p38／JNK激活剂Anisomycin (Ani)组七组。建立急性心肌梗死再灌注模型,根据分组在缺血结束前5min经颈静脉持续注射相应药物,缺血结束时注射完毕。在不同时间点处死大鼠分别测定心肌凋亡、坏死、梗死面积和凋亡途径分子的表达。结果SP和SB组较R／I组血流动力学指标显著改善,细胞凋亡和坏死减轻,心肌梗死面积减少,同时伴随凋亡信号分子降低(P<0.05)；SP和SB组同Post组相比上述指标均无明显差异。SP组P-JNK显著低于R／I组(P<0.05),同Post组相似(P>0.05)；SB组P-p38显著低于R／I组(P<0.05),同Post组相似(P>0.05)。Ani+Post组部分抵消了Post组的心肌保护效应,Post组各指标均显著优于Ani+Post组(P<0.05)；Ani组各项指标均与R／I组相似(P>0.05)。结论机械后适应可以抑制p38/JNK MAPK在心肌再灌注损伤中的磷酸化,并通过P-p38和P-JNK的减少抑制了细胞死亡受体途径和线粒体途径凋亡的发生。
第二部分机械后适应改良方案-渐进延长再灌注模式减轻心肌缺血再灌注损伤及其机制的研究
目的探讨后适应不同模式对大鼠急性心肌缺血再灌注损伤的影响并进一步研究其机制。方法60只雄性大鼠随机分为假手术组、缺血再灌注组(R／I)、后适应渐进缩短再灌注组(GDR)、后适应相等再灌注组(ER)和后适应渐进延长再灌注组(GIR)五组。建立急性心肌梗死再灌注和缺血后适应模型,根据分组给予不同后适应处理,在不同时间点处死大鼠分别测定心肌凋亡、坏死、梗死面积和凋亡途径分子的表达。结果三种后适应处理组较R／I组均可显著改善血流动力学指标、减轻细胞凋亡和坏死、限制心肌梗死面积；同时伴随P-p38,P-JNK等致凋亡分子表达显著减少(P<0.05)。上述变化GIR组最为明显,其次是ER组,GDR组最不显著。GIR组同ER组相比,除心肌梗死面积减轻未达显著性差异外(P>0.05),上述指标均明显优于ER组(P<0.05)。以上指标GIR组均显著优于GDR组(P<0.05)。结论后适应渐进延长再灌注模式能发挥更大程度的心肌保护作用,这可能与其更大程度激活ERK、抑制p38／JNK活化、抑制细胞死亡受体和线粒体凋亡途径相关。
第三部分乳酸和低剂量依达拉奉联合药物后适应减轻心肌缺血再灌注损伤及其机制的研究
目的探讨乳酸和低剂量氧自由基清除剂依达拉奉能否模拟后适应发挥有效的心肌保护作用并进一步研究其机制。方法108只雄性大鼠随机分为假手术组、缺血再灌注组(R／I)、后适应组(Post)、乳酸组(Lac)、低剂量依达拉奉组(Eda)、乳酸+低剂量依达拉奉组(Lac+Eda)六组。建立急性心肌梗死再灌注模型,在再灌注即刻使用微量注射器根据不同组别,在梗死边缘注射不同药物或生理盐水。测定再灌注10min后右心房血浆pH值,在不同时间点处死大鼠分别测定心肌凋亡、坏死、梗死面积和凋亡途径分子的表达。结果Lac和Lac+Eda组右心房血浆pH值较Post组相似(P>0.05)；Lac+Eda组再灌注1h和6h后线粒体吸光度较Post组相似(P>0.05),而Lac组在再灌注6h后期线粒体吸光度显著低于Post组(P<0.05)。Eda和Lac+Eda组MDA和SOD含量均与Post组相似(P>0.05)。Lac+Eda组较R／I组可显著改善血流动力学,减轻细胞凋亡和坏死,限制心肌梗死面积,同时伴随各凋亡途径分子表达显著减少(P<0.05)；且同Post组相比上述指标均无明显差异(P>0.05)。Lac和Eda组在上述指标方面较R／I组部分改善,但同Post组相比仍有明显差异(P<0.05)。结论局部注射乳酸能较好模拟后适应带来的酸中毒延长,局部注射低剂量依达拉奉能较好模拟后适应开始时合成的适量氧自由基；乳酸和低剂量依达拉奉联合使用可较好模拟后适应上游触发因子,有效减轻再灌注损伤。
Part One:The Change of Phospho-p38/JNK and Its Influence on Myocardial Reperfusion Injury in Mechanical Postconditioning
Objective:Study the change of Phospho-p38/JNK MAPK and its influence on myocardial reperfusion injury in mechanical postconditioning. Methods:70 rats were randomly divided into 7 groups:sham, reperfusion/injury(R/I), postconditioning (Post), SP600125 (SP), SB203580 (SB), Anisomycin+Post (Ani+Post) and Anisomycin (Ani). Results:Compared with R/I group, the level of serum marker, apoptotic index, infarct size, the expression of molecules leading to apoptosis in SP and SB group were all significantly lower (P< 0.05). The expression of P-JNK in SP group was lower than R/I group (P<0.05) and similar with Post group (P>0.05). The expression of P-p38 in SB group was lower than R/I group (P<0.05) and similar with Post group (P>0.05). On the other hand Ani+Post group lost cardioprotection partly, all variables in Ani group were similar with those in R/I group (P>0.05). Conclusion:Postconditioning could inhibit phosphorylation of p38/JNK MAPK, through which it attenuates cardiomyocyte apoptosis by both death receptor and mitochondria pathway.
Part Two:Improved Algorithm-Gradual Increased Reperfusion in Postconditioning Plays Better Role in Cardioprotection
Objective:Study cardioprotection of different postconditioning algorithm, and investigate the mechanism in the process. Methods:60 rats were randomly divided into 5 groups:sham, reperfusion/injury(R/I), postconditioning (Post), gradual decreased reperfusion (GDR), equal reperfusion(ER), and gradual increased reperfusion (GIR). Results:Compared with R/I group, the level of homodynamic variables, serum marker of myocardium, apoptotic index, infarct size, the expression molecules leading to apoptosis in GDR, ER and GIR group were lower significantly (P<0.05). The difference of GIR was the most, and then was ER and the last was GDR group. Compared with ER group, except for infarct size was similar (P>0.05), variables in GDR group were all much better (P <0.05). Conclusion:Gradual increased reperfusion algorithm of postconditioning could relieve reperfusion injury more significantly, this is probably because it could activate ERK and inhibit p38/JNK MAPK more seriously.
Part Three:Pharmacological Postconditioning with Lactic Acid and Low Dose of Edaravone could Attenuate Myocardial Reperfusion Injury
Objective:The aim of this study was to test the hypothesis that pharmacological postconditioning with lactic acid and low dose of edaravone could mimic the upper trigger of mechanical postconditioning and relieve reperfusion injury. Methods:108 rats were randomly divided into 6 groups:sham, reperfusion/injury(R/I), postconditioning (Post), lactic acid (Lac), low dose of edaravone (Eda), and lactic acid+low dose of edaravone edaravone (Lac+Eda).
Results:Compared with Post group, pH of blood from right atrium in Lac and Lac+Eda group were similar (P>0.05); and the level of MDA and SOD in Eda and Lac+Eda group were also similar (P>0.05). The level of homodynamic variables, serum marker of myocardium, apoptotic index, infarct size, the expression molecules leading to apoptosis in Lac+Eda group were all similar with Post group(P>0.05). Lac and Eda group could mimic the cardioprotection partly.
Conclusion:Lactic acid injected in ischemic myocardium at the onset of reperfusion could mimic the prolonged local acidosis in postconditioning, and pharmacological postconditioning with lactic acid and low dose of edaravone could mimic the upper trigger of mechanical postconditioning and attenuate myocardial reperfusion injury.
引文
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4 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112:2143-2148.
5 Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117:1037-1044.
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15 Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895-1903.
16 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 research in cardio logy 2008;103:464-471.
1 Penna C, Mancardi D, Raimondo S, et al. The paradigm of postconditioning to protect the heart. Journal of cellular and molecular medicine 2008;12:435-458.
2 Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Journal of the American College of Cardiology 2004;44:1103-1110.
3 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.
4 Vinten-Johansen J, Zhao ZQ, Zatta AJ, et al. Postconditioning-A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic research in cardiology 2005;100:295-310.
5 Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovascular research 2005;67:124-133.
6 Penna C, Cappello S, Mancardi D, et al. Post-conditioning reduces infarct size in the isolated rat heart:role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic research in cardiology 2006; 101:168-179.
7 Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke; a journal of cerebral circulation 2008;39:983-990.
8 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.
9 Liu XH, Zhang ZY, Sun S, et al. Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock (Augusta, Ga 2008;30:422-427.
10 张国明,王禹,李天德等.应激活化蛋白激酶在大鼠缺血后适应中的变化及其对细胞凋亡影响的研究.浙江大学学报·医学版2009：38：611-619.
11 Kuwana T, Newmeyer DD. Bcl-2-family proteins and the role of mitochondria in apoptosis. Current opinion in cell biology 2003;15:691-699.
12 Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circulation research 2004;95:957-970.
13 Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem 2007;20:1-22.
1 Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895-1903.
2 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 research in cardiology 2008;103:464-471.
3 Inserte J, Barba I, Hernando V, et al. Effect of acidic reperfusion on prolongation of intracellular acidosis and myocardial salvage. Cardiovascular research 2008;77:782-790.
4 Fujita M, Asanuma H, Hirata A, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning. American journal of physiology 2007;292:H2004-2008.
5 Rodriguez-Sinovas A, Cabestrero A, Garcia Del Blanco B, et al. Intracoronary acid infusion as an alternative to ischemic postconditioning in pigs. Basic research in cardiology 2009.
6 Gross GJ, Gauthier KM, Moore J, et al. Evidence for role of epoxyeicosatrienoic acids in mediating ischemic preconditioning and postconditioning in dog. American journal of physiology 2009;297:H47-52.
7 Katragadda D, Batchu SN, Cho WJ, et al. Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells. Journal of molecular and cellular cardiology 2009;46:867-875.
8 Abe T, Unno M, Takeuchi H, et al. A new free radical scavenger, edaravone, ameliorates oxidative liver damage due to ischemia-reperfusion in vitro and in vivo. J Gastrointest Surg 2004;8:604-615.
9 Amemiya S, Kamiya T, Nito C, et al. Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats. European journal of pharmacology 2005;516:125-130.
10 Correa F, Soto V, Zazueta C. Mitochondrial permeability transition relevance for apoptotic triggering in the post-ischemic heart. The international journal of biochemistry & cell biology 2007;39:787-798.
11 Wang C, Neff DA, Krolikowski JG, et al. The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesthesia and analgesia 2006;102:1355-1360.
12 Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion-a target for cardioprotection. Cardiovascular research 2004;61:372-385.
13 Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Journal of the American College of Cardiology 2004;44:1103-1110.
14 Darling CE, Jiang R, Maynard M, et al. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts:role of ERK1/2. American journal of physiology 2005;289:H1618-1626.
15 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.
1 Jennings RB, Sommers HM, Smyth GA, et al. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Archives of pathology 1960;70:68-78.
2 Braunwald E, Kloner RA. The stunned myocardium:prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-1149.
3 Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. American journal of physiology 2003;285:H579-588.
4 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112:2143-2148.
5 Heusch G, Buchert A, Feldhaus S, et al. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic research in cardiology 2006;101:354-356.
6 Zhu M, Feng J, Lucchinetti E, et al. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovascular research 2006;72:152-162.
7 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损伤的观察中华心血管病杂志 2006：34：685-689.
8 Philipp S, Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovascular research 2006;70:308-314.
9 范谦,杨新春,王树岩等.“渐处理”降低了犬心肌缺血／再灌注损伤中华心血管病杂志 2006：34：363-366.
10 Iliodromitis EK, Georgiadis M, Cohen MV, et al. Protection from post-conditioning depends on the number of short ischemic insults in anesthetized pigs. Basic research in cardiology 2006; 101:502-507.
11 Schwartz LM, Lagranha CJ. Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs. American journal of physiology 2006;290:H1011-1018.
12 Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. Journal of cardiovascular pharmacology and therapeutics 2006;11:55-63.
13 Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic research in cardiology 2005; 100:57-63.
14 Sivaraman V, Mudalagiri NR, Di Salvo C, et al. Postconditioning protects human atrial muscle through the activation of the RISK pathway. Basic research in cardiology 2007;102:453-459.
15 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. American journal of physiology 2006;291:H1345-1350.
16 Vinten-Johansen J, Zhao ZQ, Zatta AJ, et al. Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic research in cardiology 2005;100:295-310.
17 Kin H, Zhao ZQ, Sun HY, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovascular research 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. Journal of the American College of Cardiology 2004;44:1103-1110.
19 Argaud L, Gateau-Roesch O, Raisky O, et al. Postconditioning inhibits mitochondrial permeability transition. Circulation 2005;111:194-197.
20 Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovascular research 2005;67:124-133.
21 Penna C, Cappello S, Mancardi D, et al. Post-conditioning reduces infarct size in the isolated rat heart:role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic research in cardiology 2006;101:168-179.
22 Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke; a journal of cerebral circulation 2008;39:983-990.
23 Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895-1903.
24 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 research in cardiology 2008;103:464-471.
25 Penna C, Rastaldo R, Mancardi D, et al. Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic research in cardiology 2006;101:180-189.
26 Correa F, Garcia N, Gallardo-Perez J, et al. Post-conditioning preserves glycolytic ATP during early reperfusion:a survival mechanism for the reperfused heart. Cell Physiol Biochem 2008;22:635-644.
27 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. Circulation research 2004;95:230-232.
28 Sasaki N, Sato T, Ohler A, et al. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation 2000;101:439-445.
29 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.
30 Liu XH, Zhang ZY, Sun S, et al. Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock (Augusta, Ga 2008;30:422-427.
31 张国明,王禹,李天德等.应激活化蛋白激酶在大鼠缺血后适应中的变化及其对细胞凋亡影响的研究.浙江大学学报·医学版2009：38：611-619.
32 Yong QC, Lee SW, Foo CS, et al. Endogenous hydrogen sulphide mediates the cardioprotection induced by ischemic postconditioning. American journal of physiology 2008;295:H1330-H1340.
33 Boengler K, Buechert A, Heinen Y, et al. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circulation research 2008;102:131-135.
34 Goodman MD, Koch SE, Fuller-Bicer GA, et al. Regulating RISK:a role for JAK-STAT signaling in postconditioning? American journal of physiology 2008;295:H1649-1656.
35 Bopassa JC, Ferrera R, Gateau-Roesch O, et al. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovascular research 2006;69:178-185.
36 张振英,刘秀华,郭晓笋等.钙网蛋白参与缺血后处理减轻大鼠骨骼肌缺血／再灌注损伤生理学报,2007；59：643-650.
37 徐菲菲,刘秀华,张振英等.缺氧后处理诱导钙网蛋白表达上调的心肌保护机制研究.生理学报,2009；61：35-42.
38 Liu X, Xu F, Fu Y, et al. Calreticulin induces delayed cardioprotection through mitogen-activated protein kinases. Proteomics 2006;6:3792-3800.
39 Li Y, Ge X, Liu X. The cardioprotective effect of postconditioning is mediated by ARC through inhibiting mitochondrial apoptotic pathway. Apoptosis 2009;14:164-172.
40 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 research in cardiology 2005;100:404-412.
41 Andreka G, Vertesaljai M, Szantho G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. Heart (British Cardiac Society) 2007;93:749-752.
42 Zhao ZQ, Vinten-Johansen J. Postconditioning:reduction of reperfusion-induced injury. Cardiovascular research 2006;70:200-211.
43 张永明,王禹,刘秀华等.依达拉奉药物后处理对急性心肌缺血再灌注损伤保护作用的实验研究.中华医学杂志2008：88：2558-2561
44 张国明,王禹,李天德等.乳酸对大鼠急性心肌缺血再灌注损伤后适应的心肌保护作用.中国循环杂志2010：25：34-37.
45 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.
46 Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117:1037-1044.
2 Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. American journal of physiology 2003;285:H579-588.
3 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112:2143-2148.
4 Zhu M, Feng J, Lucchinetti E, et al. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovascular research 2006;72:152-162.
5 Philipp S, Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovascular research 2006;70:308-314.
6 Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117:1037-1044.
7 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. Circulation research 2004;95:230-232.
8 Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Journal of the American College of Cardiology 2004:44:1103-1110.
9 Bopassa JC, Ferrera R, Gateau-Roesch O, et al. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovascular research 2006:69:178-185.
10 Argaud L, Gateau-Roesch O, Raisky O, et al. Postconditioning inhibits mitochondrial permeability transition. Circulation 2005;111:194-197.
11 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.
12 Liu XH, Zhang ZY, Sun S, et al. Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock (Augusta, Ga 2008;30:422-427.
13 Penna C, Mancardi D, Raimondo S, et al. The paradigm of postconditioning to protect the heart. Journal of cellular and molecular medicine 2008;12:435-458.
14 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.
15 Vinten-Johansen J, Zhao ZQ, Zatta AJ, et al. Postconditioning-A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic research in cardiology 2005;100:295-310.
16 Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovascular research 2005;67:124-133.
17 Penna C, Cappello S, Mancardi D, et al. Post-conditioning reduces infarct size in the isolated rat heart:role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic research in cardiology 2006; 101:168-179.
18 Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke; a journal of cerebral circulation 2008;39:983-990.
19 Hausenloy DJ, Yellon DM. Survival kinases in ischemic preconditioning and postconditioning. Cardiovascular research 2006;70:240-253.
20 Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895-1903.
1 赵秀梅,孙胜,刘秀华.垫扎球囊法复制大鼠在体心肌缺血／再灌注模型.中国微循环 2007：11：206-208.
2 Li Y, Ge X, Liu X. The cardioprotective effect of postconditioning is mediated by ARC through inhibiting mitochondrial apoptotic pathway. Apoptosis 2009;14:164-172.
3 Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. American journal of physiology 2003;285:H579-588.
4 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112:2143-2148.
5 Thibault H, Piot C, Staat P, et al. Long-term benefit of postconditioning. Circulation 2008;117:1037-1044.
6 Heusch G, Buchert A, Feldhaus S, et al. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic research in cardiology 2006;101:354-356.
7 张永明,王禹,刘秀华等.依达拉奉药物后处理对急性心肌缺血再灌注损伤保护作用的实验研究.中华医学杂志2008：88：2558-2561.
8 Kaiser RA, Bueno OF, Lips DJ, et al. Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. The Journal of biological chemistry 2004;279:15524-15530.
9 Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell research 2005;15:11-18.
10 Kunapuli S, Rosanio S, Schwarz ER. "How do cardiomyocytes die?" apoptosis and autophagic cell death in cardiac myocytes. Journal of cardiac failure 2006;12:381-391.
11 Wang C, Neff DA, Krolikowski JG, et al. The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesthesia and analgesia 2006;102:1355-1360.
12 Degli Esposti M, Dive C. Mitochondrial membrane permeabilisation by Bax/Bak. Biochemical and biophysical research communications 2003;304:455-461.
13 Kuwana T, Newmeyer DD. Bcl-2-family proteins and the role of mitochondria in apoptosis. Current opinion in cell biology 2003;15:691-699.
14 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.
15 Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895-1903.
16 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 research in cardio logy 2008;103:464-471.
1 Penna C, Mancardi D, Raimondo S, et al. The paradigm of postconditioning to protect the heart. Journal of cellular and molecular medicine 2008;12:435-458.
2 Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Journal of the American College of Cardiology 2004;44:1103-1110.
3 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.
4 Vinten-Johansen J, Zhao ZQ, Zatta AJ, et al. Postconditioning-A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic research in cardiology 2005;100:295-310.
5 Kin H, Zatta AJ, Lofye MT, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovascular research 2005;67:124-133.
6 Penna C, Cappello S, Mancardi D, et al. Post-conditioning reduces infarct size in the isolated rat heart:role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic research in cardiology 2006; 101:168-179.
7 Wang JY, Shen J, Gao Q, et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke; a journal of cerebral circulation 2008;39:983-990.
8 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.
9 Liu XH, Zhang ZY, Sun S, et al. Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock (Augusta, Ga 2008;30:422-427.
10 张国明,王禹,李天德等.应激活化蛋白激酶在大鼠缺血后适应中的变化及其对细胞凋亡影响的研究.浙江大学学报·医学版2009：38：611-619.
11 Kuwana T, Newmeyer DD. Bcl-2-family proteins and the role of mitochondria in apoptosis. Current opinion in cell biology 2003;15:691-699.
12 Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circulation research 2004;95:957-970.
13 Javadov S, Karmazyn M. Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem 2007;20:1-22.
1 Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 2007;115:1895-1903.
2 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 research in cardiology 2008;103:464-471.
3 Inserte J, Barba I, Hernando V, et al. Effect of acidic reperfusion on prolongation of intracellular acidosis and myocardial salvage. Cardiovascular research 2008;77:782-790.
4 Fujita M, Asanuma H, Hirata A, et al. Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning. American journal of physiology 2007;292:H2004-2008.
5 Rodriguez-Sinovas A, Cabestrero A, Garcia Del Blanco B, et al. Intracoronary acid infusion as an alternative to ischemic postconditioning in pigs. Basic research in cardiology 2009.
6 Gross GJ, Gauthier KM, Moore J, et al. Evidence for role of epoxyeicosatrienoic acids in mediating ischemic preconditioning and postconditioning in dog. American journal of physiology 2009;297:H47-52.
7 Katragadda D, Batchu SN, Cho WJ, et al. Epoxyeicosatrienoic acids limit damage to mitochondrial function following stress in cardiac cells. Journal of molecular and cellular cardiology 2009;46:867-875.
8 Abe T, Unno M, Takeuchi H, et al. A new free radical scavenger, edaravone, ameliorates oxidative liver damage due to ischemia-reperfusion in vitro and in vivo. J Gastrointest Surg 2004;8:604-615.
9 Amemiya S, Kamiya T, Nito C, et al. Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats. European journal of pharmacology 2005;516:125-130.
10 Correa F, Soto V, Zazueta C. Mitochondrial permeability transition relevance for apoptotic triggering in the post-ischemic heart. The international journal of biochemistry & cell biology 2007;39:787-798.
11 Wang C, Neff DA, Krolikowski JG, et al. The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesthesia and analgesia 2006;102:1355-1360.
12 Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion-a target for cardioprotection. Cardiovascular research 2004;61:372-385.
13 Yang XM, Proctor JB, Cui L, et al. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. Journal of the American College of Cardiology 2004;44:1103-1110.
14 Darling CE, Jiang R, Maynard M, et al. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts:role of ERK1/2. American journal of physiology 2005;289:H1618-1626.
15 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.
1 Jennings RB, Sommers HM, Smyth GA, et al. Myocardial necrosis induced by temporary occlusion of a coronary artery in the dog. Archives of pathology 1960;70:68-78.
2 Braunwald E, Kloner RA. The stunned myocardium:prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-1149.
3 Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion:comparison with ischemic preconditioning. American journal of physiology 2003;285:H579-588.
4 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005;112:2143-2148.
5 Heusch G, Buchert A, Feldhaus S, et al. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic research in cardiology 2006;101:354-356.
6 Zhu M, Feng J, Lucchinetti E, et al. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovascular research 2006;72:152-162.
7 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损伤的观察中华心血管病杂志 2006：34：685-689.
8 Philipp S, Yang XM, Cui L, et al. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovascular research 2006;70:308-314.
9 范谦,杨新春,王树岩等.“渐处理”降低了犬心肌缺血／再灌注损伤中华心血管病杂志 2006：34：363-366.
10 Iliodromitis EK, Georgiadis M, Cohen MV, et al. Protection from post-conditioning depends on the number of short ischemic insults in anesthetized pigs. Basic research in cardiology 2006; 101:502-507.
11 Schwartz LM, Lagranha CJ. Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs. American journal of physiology 2006;290:H1011-1018.
12 Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. Journal of cardiovascular pharmacology and therapeutics 2006;11:55-63.
13 Yang XM, Philipp S, Downey JM, et al. Postconditioning's protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic research in cardiology 2005; 100:57-63.
14 Sivaraman V, Mudalagiri NR, Di Salvo C, et al. Postconditioning protects human atrial muscle through the activation of the RISK pathway. Basic research in cardiology 2007;102:453-459.
15 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. American journal of physiology 2006;291:H1345-1350.
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