缺血后处理对老年大鼠急性心肌缺血再灌注损伤的保护作用及其机制的研究
|
摘要
研究背景
WHO《世界卫生统计2008》报告:在未来的二十年,随着中低收入国家人群进入老龄化,非传染性疾病的死亡率将会大幅度增长。从全球范围看,预计到2030年,死于心血管疾病的人数将从2004年的1710万增加到2340万。
冠心病( coronary heart disease, CHD )是人类死亡的主要原因之一,每年有约380万男性和340万女性死于冠心病。发生急性心肌梗死(acute myocardial infarction, AMI)后,尽早进行有效的心肌再灌注,无论是使用溶栓治疗、经皮冠状动脉介入治疗( percutaneous coronary intervention, PCI ),还是急诊冠脉搭桥( coronary artery bypass grafting, CABG )治疗都是最有效的减小心肌梗死面积和改善临床预后的策略。然而,缺血心肌恢复血流灌注的过程中,可以诱导损伤,这种现象,称为心肌缺血再灌注损伤,可以减少心肌再灌注产生的有利影响。这种形式的损伤,可以使那些在再灌注前即刻仍然存活的心肌细胞在再灌注后很快死亡。这种形式的心肌损伤本身可以诱导心肌细胞死亡和增加心肌梗死面积,或许可以部分解释为什么尽管给予最适的心肌再灌注治疗,AMI后死亡率仍然接近10%,AMI后心力衰竭的发病率仍然接近25%。A MI动物模型研究表明,最终的梗死面积,其中50%是致命的再灌注损伤引起的;这些实验模型中,许多治疗方法都显示出能够改善致命的再灌注损伤。然而,将这些能够改善再灌注损伤的实验方法运用到临床的时候,结果却令人非常失望。虽然如此,但是在2003年,赵志青教授等报告在体犬心局部缺血45 min后,再灌注开始早期给予三个循环的30 s心肌缺血/30 s心肌再灌注,可明显减小犬心肌梗死面积。并将这种心脏保护作用命名为缺血后处理( ischemic postconditioning IPost )。之后不久,Staat和Laskey分别在临床上进行PCI的AMI患者身上进行IPost,结果发现IPost能够减小心肌梗死面积达36%以及促进心肌再灌注。
虽然IPost诱导产生心脏保护作用的确切机制仍然没有完全清楚,但是发现可能是通过减轻氧化应激反应,减少细胞内Ca2 +超载,改善血管内皮功能,减少凋亡心肌细胞的死亡,减少中性粒细胞积累以及延迟中性pH的恢复。此外,发现IPost激活再灌注损伤补救激酶( reperfusion injury salvage kinase, RISK )途径,包括磷脂酰肌醇-3-激酶( phosphatidylinositol-3-kinase, PI3-K )-蛋白激酶B ( Akt )途径和细胞外信号调节激酶( extracellular signal-regulating kinases, ERK )途径。最近,一些研究发现糖原合酶激酶-3β( glycogen synthase kinase-3beta, GSK-3β) Ser9磷酸化能促进心肌对缺血再灌注损伤的耐受。
IPost保护心肌缺血再灌注损伤的大多数研究都是在成年鼠类离体心脏上进行的,并发现心脏保护信号及促细胞生存机制可能涉及PI3-K/Akt, ERK1/2以及GSK-3β等。最近有一些研究发现IPost未能保护老年小鼠心脏。但是关于IPost的保护作用能否在老年大鼠或人身上获得及相关机制还是知之甚少。
研究目的
(1)确定成年大鼠在体心脏急性缺血后再灌注即刻给予缺血后处理能否保护心脏,减轻缺血再灌注损伤。
(2)评价缺血后处理能否减轻老年大鼠在体心脏缺血再灌注后的损伤,并比较后处理保护作用在成年大鼠与老年大鼠之间的区别。
(3)初步确定老年大鼠缺血后处理的保护作用是否与心肌细胞内PI3-K/Akt及GSK-3β的磷酸化有关,如果有关,则激活PI3-K/Akt和GSK-3β可能是治疗缺血再灌注损伤的新的治疗手段。
实验方法
1.成年(3-4个月)及老年(16-18个月)雄性SD大鼠,戊巴比妥钠(50 mg/kg)腹腔麻醉后,行左侧开胸术,6-0丝线穿过左冠状动脉前降支(LAD),制备心肌缺血/再灌注大鼠模型。大鼠心脏缺血30min,再灌注3h。
2.针形电极置于大鼠四肢皮下,连续记录心电图(electrocardiogram, ECG)。自右侧颈动脉插管至左心室,记录血流动力学参数。左侧颈外静脉插管给药。
3.实验共分为10组,成年及老年大鼠各5组(n=8/成年组,n=6/老年组)。①成年大鼠缺血再灌注组( I/Radult)及老年大鼠缺血再灌注组( I/Raged):大鼠造模,缺血前后及再灌注前后不再给予其他干预;②成年大鼠缺血后处理组(IPostadult)及老年大鼠缺血后处理组(IPostaged):大鼠造模,再灌注即刻给予缺血后处理(4×10 s I/ 10 s R),再无其他干预;③成年大鼠缺血后处理联合LY294002组(IPost+LYadult)及老年大鼠缺血后处理联合LY294002组(IPost+LYaged):LY294002是选择性的PI3K抑制剂,大鼠造模,再灌注即刻给予缺血后处理(4×10 s I/ 10 s R),同时由另一术者经大鼠左侧颈外静脉给药LY294002(0.3 mg/kg),再无其他干预;④成年大鼠药物载体组(Vehicleadult)及老年大鼠药物载体组(Vehicleaged):大鼠造模,再灌注即刻给予缺血后处理,同时给予0.02%的DMSO(与IPost+LY组等容积,而不含有LY294002);⑤成年大鼠假手术组( Shamadult )及老年大鼠假手术组(Shamaged):未造模大鼠,颈部切开,气管插管,开胸,前降支下缝线等过程均同造模组,只是不进行冠脉结扎。
4.在缺血前及再灌注3 h后取血0.5 mL,离心,取血清-70℃保存,用血清肌酸激酶(CK)和乳酸脱氢酶(LDH)试剂盒检测酶活性。
5.再灌注结束时,采用Evans blue与TTC染色测量缺血区及梗死区面积。
6.上述10组,各组均额外再做4只大鼠,缺血30 min,在再灌注15 min时,取缺血区组织,采用Western Blotting方法测定缺血心肌组织Akt, GSK-3β蛋白含量及其磷酸化水平。
实验结果
1.血流动力学参数包括心率( HR )、LVDP以及±dP/dtmax
(1)心率:在所有监测的时间点I/Radult,I Postadult及IPost+LYadult组之间; I/Raged,IPostaged及IPost+LYaged组之间没有显著差异。单就I/R组而言,在基线、I 5 min,R 15 min及R 30 min时老年大鼠的心率明显低于成年大鼠组。就IPost及IPost+LY组而言,老年大鼠与成年大鼠心率没有差异。
(2)LVDP:所有监测的时间点I/Radult,IP ostadult及IPost + LYadult组之间; I/Raged,IPostaged及IPost + LYaged组之间没有显著差异。单就I/R组而言,基线、R 5min,R 1h及R 2h时老年大鼠的LVDP明显低于成年大鼠组。就IPost组而言,R 5min和R 2h时老年大鼠的LVDP明显低于成年大鼠组。就IPost+LY组而言,R 2h和R 3h时老年大鼠的LVDP明显低于成年大鼠组。
(3) +dP/dtmax: R 5min,R 2h及R 3h,IPostadult组大鼠+dP/dtmax明显高于I/Radult及IPost+LYadult。但在所有监测的时间I/Raged,IP ostaged及IPost + LYaged组之间没有显著差异。单就I/R组而言,老年大鼠与成年大鼠之间没有差别。就IPost组而言,整个再灌注期间除了R 1h时,老年大鼠的+dP/dtmax明显低于成年大鼠。就IPost+LY组而言,只是在R 30min时老年大鼠的+dP/dtmax明显低于成年大鼠组。
(4) -dP/dtmax: R 2h及R 3h,IPostadult组大鼠-dP/dtmax明显高于I/Radult及IPost+LYadult。但在所有监测的时间I/Raged,IPostaged及IPost+LYaged组之间没有显著差异。在I/R组和IPost+LY组,只有I 5min时,老年大鼠的-dP/dtmax明显高于成年大鼠。但在IPost组,R 5min和R 15min时,老年大鼠的-dP/dtmax都明显低于成年大鼠组。
2.冠脉LAD阻塞后缺血危险区(area at risk , AAR以%LV表示)在除Sham组外的其余各组之间是可比的(I/Radult,52.8±5.2%;IPostadult, 52.0±5.0%;IPost+LYadult ,52.2±5.8%;I/Raged, 51.3±7.2%;IPostaged, 53.8±3.5%;IPost+LYaged,51.1±5.8%;所有P =NS)。正如所期望的,与I/R组相比,IPost明显减小梗死面积(Infarct size,IS;以%AAR表示) (IPostadult vs. I/Radult:11.9±1.6% vs. 30.2±2.8%,P<0.05;IPostaged vs. I/Raged:13.7±2.5% vs. 27.5±3.5%,P<0.05)。再灌注同时给予PI3K抑制剂LY294002,结果取消IPost的减小IS的作用(IPost+LYadult vs. IPostadult: 30.1±2.9% vs. 11.9±1.6%,P<0.05;IPost + LYaged vs. IPostaged:33.4±7.0% vs. 13.7±2.5%,P <0.05)。而在I/Radult组与I/Raged组、IP ostadult组与IPostaged组、IP ost+LYadult组与IPost+LYaged组IS之间均无统计学差异(所有P =NS)。
3.在术前,老年组血清CK的水平均明显低于成年组,LDH水平老年与成年组之间均无差异。术前,CK与LDH水平在老年组内部及成年组内部各组间也无差异。与术前相比,再灌注3 h后各组CK及LDH水平显著升高(所有P<0.05)。再灌注3 h后IPost组CK与LDH水平升高幅度均显著低于I/R组(所有P<0.05)。给予PI3K抑制剂LY294002后,CK与LDH水平升高幅度均比IPost组高(所有P<0.05),但与I/R组之间无统计学差异。
4.任两组间总Akt(t-Akt)与总GSK-3β(t-GSK-3β)水平无差异。但是不论是成年组大鼠还是老年组,与I/R组相比,IPost均显著增加p-Akt水平(p-Akt/t-Akt: IPostadult vs. I/Radult: 0.64±0.04 vs. 0.40±0.09,P<0.05; IPostaged vs. I/Raged:0.63±0.03 vs. 0.39±0.01, P<0.05)。给予LY294002后可阻断Akt磷酸化(p-Akt/t-Akt:IPost + LYadult vs. IPostadult: 0.34±0.07 vs. 0.64±0.04,P<0.05;IPost + LYaged vs. IPostaged:0.35±0.09 vs 0.63±0.03, P<0.05)。同样,IPost也明显增加GSK-3β磷酸化水平,而LY294002则阻断GSK-3β的磷酸化。
结论
1.再灌注即刻给予缺血后处理能够减小成年SD大鼠心肌梗死面积,降低CK及LDH升高水平,并能够部分改善心脏功能。
2.缺血后处理可减小老年SD大鼠急性缺血/再灌注时心肌梗死面积,降低CK及LDH升高水平,但未能改善心脏功能。
3.缺血后处理对成年及老年大鼠心脏保护作用可能与Akt及GSK-3β磷酸化有关。
Background
As populations age in middle- and low-income countries over the next 25 years, the proportion of deaths due to noncommunicable diseases will rise significantly. Globally, deaths from cancer will increase from 7.4 million in 2004 to 11.8 million in 2030, and deaths from cardiovascular diseases will rise from 17.1 million to 23.4 million in the same period ( world health statistics 2008 ).
Coronary heart disease is the leading cause of death worldwide, and 3.8 million men and 3.4 million women die of the disease each year. After an acute myocardial infarction, early and successful myocardial reperfusion with the use of thrombolytic therapy or primary percutaneous coronary intervention ( PCI ) or emergency coronary artery bypass grafting ( CABG ) is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. The process of restoring blood flow to the ischemic myocardium, however, can induce injury. This phenomenon, termed myocardial reperfusion injury, can paradoxically reduce the beneficial effects of myocardial reperfusion. The injury culminates in the death of cardiac myocytes that were viable immediately before myocardial reperfusion. This form of myocardial injury, which by itself can induce cardiomyocyte death and increase infarct size ,may in part explain why, despite optimal myocardial reperfusion, the rate of death after an acute myocardial infarction approaches 10%, and the incidence of cardiac failure after an acute myocardial infarction is almost 25%.Studies in animal models of acute myocardial infarction suggest that lethal reperfusion injury accounts for up to 50% of the final size of a myocardial infarct, and in these models a number of strategies have been shown to ameliorate lethal reperfusion injury. Yet, the translation of these beneficial effects into the clinical setting has been disappointing. But in 2003, Prof Zhao Zhiqing et al. showed that after a 45-minute episode of sustained myocardial ischemia, the interruption of myocardial reperfusion with three 30-second cycles of myocardial ischemia and reperfusion could reduce the myocardial infarct size significantly. They named this form of cardioprotection ischemic postconditioning. Shortly after that,Staat and Laskey respectively used ischemic postconditioning in patients with acute myocardial infarction who are undergoing PCI with a protocol that has reduced myocardial infarct size by 36% and improved myocardial reperfusion.
Although the precise mechanism of ischemic postconditioning–induced protection is not fully understood, but the procedure has been shown to target the important mediators of lethal reperfusion injury by reducing oxidative stress, decreasing intracellular Ca2 + overload, improving endothelial function, attenuating apoptotic cardiomyocyte death, reducing neutrophil accumulation, and delaying the restoration of neutral pH. Furthermore, ischemic postconditioning activates the reperfusion injury salvage kinase (RISK) pathway, which include the phosphatidylinositol-3-kinase-Akt pathway ( PI3K-Akt ) and the extracellular signal-regulating kinases ( ERK ) pathway. Recently, several studies have suggested that phosphorylation of glycogen synthase kinase-3beta (GSK-3β) at Ser9 enhances myocardial tolerance during ischemia- reperfusion injury.
In the majority of studies, ischemic postconditioning (IPost) has been demonstrated to protect adult rodent hearts from myocardium ischemia- reperfusion (I/R) injury in vitro, and has implicated the involvement of several candidate signaling pathways such as PI3-K/Akt, ERK1/2, and GSK-3βin cardioprotective signaling and pro-cell survival mechanisms. Recently, some researches have found that the cardioprotection of IPost is lost in aged mice. However, little is known with regards to these signaling mechanisms during advanced age.
Aim
(1) to determine whether ischemic postconditioning applied at the beginning of reperfusion could protect adult hearts in vivo from ischemia reperfusion injury .
(2) to evaluate the hypothesis that ischemic postconditioning could protect ischemia/reperfusion aged hearts in vivo. And to compare the cardioprotection effects of ischemic postconditioning between aged and adult heats.
(3) to investigate whether IPost’s cardioprotection is dependent on the activation of PI3-K/Akt and GSK-3β, and if activation of PI3-K/Akt or GSK-3βmay be a novel therapeutic strategy for reducing myocardial I/R injury.
Methods
1. Male Sprague Dawley (SD) rats (adult, 3-4 months aged, 16-18 months) were anesthetized with sodium pentobarbital (50 mg/kg, i.p.), and experienced left thoracotomy. a 6-0 silk suture was placed under the left anterior descending coronary artery (LAD), and ends of the suture were threaded through a segment of polyethylene tube to form a snare for the reversible LAD occlusion. Rats were subiected to 30 min myocardial ischemia and 3 h reperfusion.
2. Needle electrodes were placed subcutaneously on the limbs, and an electrocardiogram was continuously recorded.the right carotid artery was cannulated with a 24-gauge angiocath connected to a fluid-filled pressure transducer for monitoring Hemodynamic properties. The left external jugular vein was cannulated for drug administration.
3. The rats were assigned to one of the following groups based upon the intervention performed (n = 8 per adult group, n = 6 per aged group): (1) I/Radult and I/Raged: received no other intervention either before or after LAD occlusion (2) IPostadult and IPostaged: received ischemic postconditioning induced by four cycles of 10 seconds of ischemia and 10 seconds of reperfusion at the beginning of reperfusion (3) IPost+LYadult and IPost+LYaged: received ischemic postconditioning in the presence of the selective PI3K inhibitor, LY294002 (0.3 mg/kg) administered via the left external jugular vein immediately at the beginning of reperfusion (4) Vehicleadult and Vehicleaged: received ischemic postconditioning in the presence of an equal volume of vehicle, 0.02% dimethyl sulfoxide (DMSO) without LY294002 at the beginning of reperfusion (5) Shamadult and Shamaged:p lacement of the silk suture under the LAD and no other intervention.
4. Blood samples (0.5 mL) were collected at baseline and the end of reperfusion and centrifuged at 2500×g and 4°C for 10 min. The samples were then stored at -70°C until further study. The activity of CK and LDH was analyzed at 25°C using commercially available kits.
5. At the end of reperfusion,ischemic and infarct areas were measured by Evans blue and triphenyltetrazolium chloride ( TTC ) staining respectively.
6. In separate experiments (n=4 rats per experimental group), phosphorylation of Akt and GSK-3βwere analyzed by Western blotting after 15 min of reperfusion.
Results
1. Hemodynamic data includes heart rate ( HR ), LVDP and±dP/dtmax (1) HR: At all time points, there were no significant differences among I/Radult, IPostadult, and IPost+LYadult groups, and no significant differences among the I/Raged, IPostaged, and IPost+LYaged groups. At baseline, I 5 min, R 15 min, R 30 min, the HR of I/Raged group were lower than that of I/Radult group. At all time points, there were no significant differences between IPostadult,and IPostaged , between IPost+LYadult and IPost+LYaged group.
(2) LVDP: At all time points, there were no significant differences among I/Radult, IPostadult, IPost+LYadult groups, and no significant differences among the I/Raged, IPostaged, IPost+LYaged groups. At points of R 5 min, R1 h, and R 2 h, the LVDP of I/Raged group were lower than that of I/Radult group. At points of R 5 min, R 2 h, the LVDP of IPostaged group were lower than that of IPostadult group. At points of R 2 h and R 3 h, the LVDP of IPost+LYaged group were lower than that of IPost+LYadult group.
(3) +dP/dtmax:At R 5 min, R 2 h, and R 3 h, +dP/dtmax of IPostadult were significantly higher than that of I/Radult or IPost+LYadult. But at all time points, there were no significant differences among the I/Raged, IPostaged, IPost+LYaged groups. In the I/Rgroup, there was no significant difference between aged and adult rats. But in the IPost groups, +dP/dtmax of adult rats were significantly higher than that of aged rats during reperfusion except R 1 h. In the IPost+LY groups only at R 30 min +dP/dtmax of adult rats were significantly higher than that of aged rats.
(4) -dP/dtmax: At R2 h, R 3 h, -dP/dtmax of IPostadult were significantly higher than that of I/Radult or IPost+LYadult. But at all time points, there were no significant differences among the I/Raged, IPostaged, IPost+LYaged groups. In the I/R and IPost+LY group, only at I 5 min -dP/dtmax of adult rats were significantly lower than that of aged rats. But in the IPost groups, -dP/dtmax of adult rats were significantly higher than that of aged rats at R 5 min and R 15 min.
2. The area at risk ( in percentage of the left ventricle ) by LAD occlusion was comparable among six groups ( I/Radult, 52.8±5.2% IPostadult, 52.0±5.0% Ipost + LYadult, 52.2±5.8% I/Raged, 51.3±7.2% IPostaged, 53.8±3.5% IPost+LYaged, 51.1±5.8% ). As expected, the postconditioned hearts developed significantly smaller infarct sizes ( expressed as percentage of the area at risk, IS/AAR ) than I/R hearts (11.9±1.6% in IPostadult vs. 30.2±2.8% in I/Radult, P<0.05 13.7±2.5% in IPostaged vs. 27.5±3.5% in I/Raged, P<0.05 ). The PI3K inhibitor, LY294002, abolished IPost’s cardioprotection in aged and adult rats (30.1±2.9% in IPost + LYadult vs. 11.9±1.6% in IPostadult, P<0.05; 33.4±7.0% in IPost + LYaged vs. 13.7±2.5% in IPostaged, P<0.05 ). There were no significant differences between I/Radult and I/Raged, IPostadult and IPostaged, IPost + LYadult and IPost+LYaged. ( all P =NS ).
3. At baseline, the levels of CK in aged groups were lower than that in adult groups, and no differences within aged groups and within adult groups. The levels LDH were no differences between the six groups. Compared with the baseline, CK and LDH release was significantly increased after 3 hours of reperfusion in all I/R, IPost, and IPost+LY groups ( all P < 0.05 vs. baseline ). At 3 h of reperfusion, CK and LDH release in IPost rats was significantly lower than that in I/R groups ( all P< 0.05 vs. I/R groups ). LY294002 prevented the decrease of CK and LDH release in IPost group ( all P<0.05 vs. IPost, not significantly different from I/R groups ).
4. There were no differences in total Akt ( t-Akt ) and total GSK-3β( t-GSK-3β) levels between every two groups. But in both adult and aged rat hearts, IPost significantly increased levels of Akt phosphorylation to levels greater than I/R hearts ( p-Akt/t-Akt: 0.64±0.04 in IPostadult vs. 0.40±0.09 in I/Radult, P<0.05 0.63±0.03 in IPostaged vs. 0.39±0.01 in I/Raged, P<0.05 ). The PI3K inhibitor, LY294002, blocked Akt phosphorylation ( p-Akt/t-Akt: 0.34±0.07 in IPost + LYadult vs. 0.64±0.04 in IPostadult, P<0.05 0.35±0.09 in IPost + LYaged vs. 0.63±0.03 in IPostaged ,P<0.05 ). Similarly, IPost significantly increased levels of GSK-3βphosphorylation to levels greater than I/R hearts, and LY294002 attenuated the levels of phosphorylated-GSK-3βin both adult and aged hearts.
Conclusion
1. Ischemic postconditioning at the onset of reperfusion reduces myocardial infarct size, attenuates the increased levels of CK and LDH, and improve functional preservation after reperfusion in adult SD rats in vivo.
2. An infarct sparing effect for IPost in in vivo heart model of aged rats, which unlike the adult rat model, was not associated with functional preservation.
3. IPost’s cardioprotection in both adult and aged SD rat hearts may be associated with Akt and GSK-3βphosphorylation.
WHO《世界卫生统计2008》报告:在未来的二十年,随着中低收入国家人群进入老龄化,非传染性疾病的死亡率将会大幅度增长。从全球范围看,预计到2030年,死于心血管疾病的人数将从2004年的1710万增加到2340万。
冠心病( coronary heart disease, CHD )是人类死亡的主要原因之一,每年有约380万男性和340万女性死于冠心病。发生急性心肌梗死(acute myocardial infarction, AMI)后,尽早进行有效的心肌再灌注,无论是使用溶栓治疗、经皮冠状动脉介入治疗( percutaneous coronary intervention, PCI ),还是急诊冠脉搭桥( coronary artery bypass grafting, CABG )治疗都是最有效的减小心肌梗死面积和改善临床预后的策略。然而,缺血心肌恢复血流灌注的过程中,可以诱导损伤,这种现象,称为心肌缺血再灌注损伤,可以减少心肌再灌注产生的有利影响。这种形式的损伤,可以使那些在再灌注前即刻仍然存活的心肌细胞在再灌注后很快死亡。这种形式的心肌损伤本身可以诱导心肌细胞死亡和增加心肌梗死面积,或许可以部分解释为什么尽管给予最适的心肌再灌注治疗,AMI后死亡率仍然接近10%,AMI后心力衰竭的发病率仍然接近25%。A MI动物模型研究表明,最终的梗死面积,其中50%是致命的再灌注损伤引起的;这些实验模型中,许多治疗方法都显示出能够改善致命的再灌注损伤。然而,将这些能够改善再灌注损伤的实验方法运用到临床的时候,结果却令人非常失望。虽然如此,但是在2003年,赵志青教授等报告在体犬心局部缺血45 min后,再灌注开始早期给予三个循环的30 s心肌缺血/30 s心肌再灌注,可明显减小犬心肌梗死面积。并将这种心脏保护作用命名为缺血后处理( ischemic postconditioning IPost )。之后不久,Staat和Laskey分别在临床上进行PCI的AMI患者身上进行IPost,结果发现IPost能够减小心肌梗死面积达36%以及促进心肌再灌注。
虽然IPost诱导产生心脏保护作用的确切机制仍然没有完全清楚,但是发现可能是通过减轻氧化应激反应,减少细胞内Ca2 +超载,改善血管内皮功能,减少凋亡心肌细胞的死亡,减少中性粒细胞积累以及延迟中性pH的恢复。此外,发现IPost激活再灌注损伤补救激酶( reperfusion injury salvage kinase, RISK )途径,包括磷脂酰肌醇-3-激酶( phosphatidylinositol-3-kinase, PI3-K )-蛋白激酶B ( Akt )途径和细胞外信号调节激酶( extracellular signal-regulating kinases, ERK )途径。最近,一些研究发现糖原合酶激酶-3β( glycogen synthase kinase-3beta, GSK-3β) Ser9磷酸化能促进心肌对缺血再灌注损伤的耐受。
IPost保护心肌缺血再灌注损伤的大多数研究都是在成年鼠类离体心脏上进行的,并发现心脏保护信号及促细胞生存机制可能涉及PI3-K/Akt, ERK1/2以及GSK-3β等。最近有一些研究发现IPost未能保护老年小鼠心脏。但是关于IPost的保护作用能否在老年大鼠或人身上获得及相关机制还是知之甚少。
研究目的
(1)确定成年大鼠在体心脏急性缺血后再灌注即刻给予缺血后处理能否保护心脏,减轻缺血再灌注损伤。
(2)评价缺血后处理能否减轻老年大鼠在体心脏缺血再灌注后的损伤,并比较后处理保护作用在成年大鼠与老年大鼠之间的区别。
(3)初步确定老年大鼠缺血后处理的保护作用是否与心肌细胞内PI3-K/Akt及GSK-3β的磷酸化有关,如果有关,则激活PI3-K/Akt和GSK-3β可能是治疗缺血再灌注损伤的新的治疗手段。
实验方法
1.成年(3-4个月)及老年(16-18个月)雄性SD大鼠,戊巴比妥钠(50 mg/kg)腹腔麻醉后,行左侧开胸术,6-0丝线穿过左冠状动脉前降支(LAD),制备心肌缺血/再灌注大鼠模型。大鼠心脏缺血30min,再灌注3h。
2.针形电极置于大鼠四肢皮下,连续记录心电图(electrocardiogram, ECG)。自右侧颈动脉插管至左心室,记录血流动力学参数。左侧颈外静脉插管给药。
3.实验共分为10组,成年及老年大鼠各5组(n=8/成年组,n=6/老年组)。①成年大鼠缺血再灌注组( I/Radult)及老年大鼠缺血再灌注组( I/Raged):大鼠造模,缺血前后及再灌注前后不再给予其他干预;②成年大鼠缺血后处理组(IPostadult)及老年大鼠缺血后处理组(IPostaged):大鼠造模,再灌注即刻给予缺血后处理(4×10 s I/ 10 s R),再无其他干预;③成年大鼠缺血后处理联合LY294002组(IPost+LYadult)及老年大鼠缺血后处理联合LY294002组(IPost+LYaged):LY294002是选择性的PI3K抑制剂,大鼠造模,再灌注即刻给予缺血后处理(4×10 s I/ 10 s R),同时由另一术者经大鼠左侧颈外静脉给药LY294002(0.3 mg/kg),再无其他干预;④成年大鼠药物载体组(Vehicleadult)及老年大鼠药物载体组(Vehicleaged):大鼠造模,再灌注即刻给予缺血后处理,同时给予0.02%的DMSO(与IPost+LY组等容积,而不含有LY294002);⑤成年大鼠假手术组( Shamadult )及老年大鼠假手术组(Shamaged):未造模大鼠,颈部切开,气管插管,开胸,前降支下缝线等过程均同造模组,只是不进行冠脉结扎。
4.在缺血前及再灌注3 h后取血0.5 mL,离心,取血清-70℃保存,用血清肌酸激酶(CK)和乳酸脱氢酶(LDH)试剂盒检测酶活性。
5.再灌注结束时,采用Evans blue与TTC染色测量缺血区及梗死区面积。
6.上述10组,各组均额外再做4只大鼠,缺血30 min,在再灌注15 min时,取缺血区组织,采用Western Blotting方法测定缺血心肌组织Akt, GSK-3β蛋白含量及其磷酸化水平。
实验结果
1.血流动力学参数包括心率( HR )、LVDP以及±dP/dtmax
(1)心率:在所有监测的时间点I/Radult,I Postadult及IPost+LYadult组之间; I/Raged,IPostaged及IPost+LYaged组之间没有显著差异。单就I/R组而言,在基线、I 5 min,R 15 min及R 30 min时老年大鼠的心率明显低于成年大鼠组。就IPost及IPost+LY组而言,老年大鼠与成年大鼠心率没有差异。
(2)LVDP:所有监测的时间点I/Radult,IP ostadult及IPost + LYadult组之间; I/Raged,IPostaged及IPost + LYaged组之间没有显著差异。单就I/R组而言,基线、R 5min,R 1h及R 2h时老年大鼠的LVDP明显低于成年大鼠组。就IPost组而言,R 5min和R 2h时老年大鼠的LVDP明显低于成年大鼠组。就IPost+LY组而言,R 2h和R 3h时老年大鼠的LVDP明显低于成年大鼠组。
(3) +dP/dtmax: R 5min,R 2h及R 3h,IPostadult组大鼠+dP/dtmax明显高于I/Radult及IPost+LYadult。但在所有监测的时间I/Raged,IP ostaged及IPost + LYaged组之间没有显著差异。单就I/R组而言,老年大鼠与成年大鼠之间没有差别。就IPost组而言,整个再灌注期间除了R 1h时,老年大鼠的+dP/dtmax明显低于成年大鼠。就IPost+LY组而言,只是在R 30min时老年大鼠的+dP/dtmax明显低于成年大鼠组。
(4) -dP/dtmax: R 2h及R 3h,IPostadult组大鼠-dP/dtmax明显高于I/Radult及IPost+LYadult。但在所有监测的时间I/Raged,IPostaged及IPost+LYaged组之间没有显著差异。在I/R组和IPost+LY组,只有I 5min时,老年大鼠的-dP/dtmax明显高于成年大鼠。但在IPost组,R 5min和R 15min时,老年大鼠的-dP/dtmax都明显低于成年大鼠组。
2.冠脉LAD阻塞后缺血危险区(area at risk , AAR以%LV表示)在除Sham组外的其余各组之间是可比的(I/Radult,52.8±5.2%;IPostadult, 52.0±5.0%;IPost+LYadult ,52.2±5.8%;I/Raged, 51.3±7.2%;IPostaged, 53.8±3.5%;IPost+LYaged,51.1±5.8%;所有P =NS)。正如所期望的,与I/R组相比,IPost明显减小梗死面积(Infarct size,IS;以%AAR表示) (IPostadult vs. I/Radult:11.9±1.6% vs. 30.2±2.8%,P<0.05;IPostaged vs. I/Raged:13.7±2.5% vs. 27.5±3.5%,P<0.05)。再灌注同时给予PI3K抑制剂LY294002,结果取消IPost的减小IS的作用(IPost+LYadult vs. IPostadult: 30.1±2.9% vs. 11.9±1.6%,P<0.05;IPost + LYaged vs. IPostaged:33.4±7.0% vs. 13.7±2.5%,P <0.05)。而在I/Radult组与I/Raged组、IP ostadult组与IPostaged组、IP ost+LYadult组与IPost+LYaged组IS之间均无统计学差异(所有P =NS)。
3.在术前,老年组血清CK的水平均明显低于成年组,LDH水平老年与成年组之间均无差异。术前,CK与LDH水平在老年组内部及成年组内部各组间也无差异。与术前相比,再灌注3 h后各组CK及LDH水平显著升高(所有P<0.05)。再灌注3 h后IPost组CK与LDH水平升高幅度均显著低于I/R组(所有P<0.05)。给予PI3K抑制剂LY294002后,CK与LDH水平升高幅度均比IPost组高(所有P<0.05),但与I/R组之间无统计学差异。
4.任两组间总Akt(t-Akt)与总GSK-3β(t-GSK-3β)水平无差异。但是不论是成年组大鼠还是老年组,与I/R组相比,IPost均显著增加p-Akt水平(p-Akt/t-Akt: IPostadult vs. I/Radult: 0.64±0.04 vs. 0.40±0.09,P<0.05; IPostaged vs. I/Raged:0.63±0.03 vs. 0.39±0.01, P<0.05)。给予LY294002后可阻断Akt磷酸化(p-Akt/t-Akt:IPost + LYadult vs. IPostadult: 0.34±0.07 vs. 0.64±0.04,P<0.05;IPost + LYaged vs. IPostaged:0.35±0.09 vs 0.63±0.03, P<0.05)。同样,IPost也明显增加GSK-3β磷酸化水平,而LY294002则阻断GSK-3β的磷酸化。
结论
1.再灌注即刻给予缺血后处理能够减小成年SD大鼠心肌梗死面积,降低CK及LDH升高水平,并能够部分改善心脏功能。
2.缺血后处理可减小老年SD大鼠急性缺血/再灌注时心肌梗死面积,降低CK及LDH升高水平,但未能改善心脏功能。
3.缺血后处理对成年及老年大鼠心脏保护作用可能与Akt及GSK-3β磷酸化有关。
Background
As populations age in middle- and low-income countries over the next 25 years, the proportion of deaths due to noncommunicable diseases will rise significantly. Globally, deaths from cancer will increase from 7.4 million in 2004 to 11.8 million in 2030, and deaths from cardiovascular diseases will rise from 17.1 million to 23.4 million in the same period ( world health statistics 2008 ).
Coronary heart disease is the leading cause of death worldwide, and 3.8 million men and 3.4 million women die of the disease each year. After an acute myocardial infarction, early and successful myocardial reperfusion with the use of thrombolytic therapy or primary percutaneous coronary intervention ( PCI ) or emergency coronary artery bypass grafting ( CABG ) is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. The process of restoring blood flow to the ischemic myocardium, however, can induce injury. This phenomenon, termed myocardial reperfusion injury, can paradoxically reduce the beneficial effects of myocardial reperfusion. The injury culminates in the death of cardiac myocytes that were viable immediately before myocardial reperfusion. This form of myocardial injury, which by itself can induce cardiomyocyte death and increase infarct size ,may in part explain why, despite optimal myocardial reperfusion, the rate of death after an acute myocardial infarction approaches 10%, and the incidence of cardiac failure after an acute myocardial infarction is almost 25%.Studies in animal models of acute myocardial infarction suggest that lethal reperfusion injury accounts for up to 50% of the final size of a myocardial infarct, and in these models a number of strategies have been shown to ameliorate lethal reperfusion injury. Yet, the translation of these beneficial effects into the clinical setting has been disappointing. But in 2003, Prof Zhao Zhiqing et al. showed that after a 45-minute episode of sustained myocardial ischemia, the interruption of myocardial reperfusion with three 30-second cycles of myocardial ischemia and reperfusion could reduce the myocardial infarct size significantly. They named this form of cardioprotection ischemic postconditioning. Shortly after that,Staat and Laskey respectively used ischemic postconditioning in patients with acute myocardial infarction who are undergoing PCI with a protocol that has reduced myocardial infarct size by 36% and improved myocardial reperfusion.
Although the precise mechanism of ischemic postconditioning–induced protection is not fully understood, but the procedure has been shown to target the important mediators of lethal reperfusion injury by reducing oxidative stress, decreasing intracellular Ca2 + overload, improving endothelial function, attenuating apoptotic cardiomyocyte death, reducing neutrophil accumulation, and delaying the restoration of neutral pH. Furthermore, ischemic postconditioning activates the reperfusion injury salvage kinase (RISK) pathway, which include the phosphatidylinositol-3-kinase-Akt pathway ( PI3K-Akt ) and the extracellular signal-regulating kinases ( ERK ) pathway. Recently, several studies have suggested that phosphorylation of glycogen synthase kinase-3beta (GSK-3β) at Ser9 enhances myocardial tolerance during ischemia- reperfusion injury.
In the majority of studies, ischemic postconditioning (IPost) has been demonstrated to protect adult rodent hearts from myocardium ischemia- reperfusion (I/R) injury in vitro, and has implicated the involvement of several candidate signaling pathways such as PI3-K/Akt, ERK1/2, and GSK-3βin cardioprotective signaling and pro-cell survival mechanisms. Recently, some researches have found that the cardioprotection of IPost is lost in aged mice. However, little is known with regards to these signaling mechanisms during advanced age.
Aim
(1) to determine whether ischemic postconditioning applied at the beginning of reperfusion could protect adult hearts in vivo from ischemia reperfusion injury .
(2) to evaluate the hypothesis that ischemic postconditioning could protect ischemia/reperfusion aged hearts in vivo. And to compare the cardioprotection effects of ischemic postconditioning between aged and adult heats.
(3) to investigate whether IPost’s cardioprotection is dependent on the activation of PI3-K/Akt and GSK-3β, and if activation of PI3-K/Akt or GSK-3βmay be a novel therapeutic strategy for reducing myocardial I/R injury.
Methods
1. Male Sprague Dawley (SD) rats (adult, 3-4 months aged, 16-18 months) were anesthetized with sodium pentobarbital (50 mg/kg, i.p.), and experienced left thoracotomy. a 6-0 silk suture was placed under the left anterior descending coronary artery (LAD), and ends of the suture were threaded through a segment of polyethylene tube to form a snare for the reversible LAD occlusion. Rats were subiected to 30 min myocardial ischemia and 3 h reperfusion.
2. Needle electrodes were placed subcutaneously on the limbs, and an electrocardiogram was continuously recorded.the right carotid artery was cannulated with a 24-gauge angiocath connected to a fluid-filled pressure transducer for monitoring Hemodynamic properties. The left external jugular vein was cannulated for drug administration.
3. The rats were assigned to one of the following groups based upon the intervention performed (n = 8 per adult group, n = 6 per aged group): (1) I/Radult and I/Raged: received no other intervention either before or after LAD occlusion (2) IPostadult and IPostaged: received ischemic postconditioning induced by four cycles of 10 seconds of ischemia and 10 seconds of reperfusion at the beginning of reperfusion (3) IPost+LYadult and IPost+LYaged: received ischemic postconditioning in the presence of the selective PI3K inhibitor, LY294002 (0.3 mg/kg) administered via the left external jugular vein immediately at the beginning of reperfusion (4) Vehicleadult and Vehicleaged: received ischemic postconditioning in the presence of an equal volume of vehicle, 0.02% dimethyl sulfoxide (DMSO) without LY294002 at the beginning of reperfusion (5) Shamadult and Shamaged:p lacement of the silk suture under the LAD and no other intervention.
4. Blood samples (0.5 mL) were collected at baseline and the end of reperfusion and centrifuged at 2500×g and 4°C for 10 min. The samples were then stored at -70°C until further study. The activity of CK and LDH was analyzed at 25°C using commercially available kits.
5. At the end of reperfusion,ischemic and infarct areas were measured by Evans blue and triphenyltetrazolium chloride ( TTC ) staining respectively.
6. In separate experiments (n=4 rats per experimental group), phosphorylation of Akt and GSK-3βwere analyzed by Western blotting after 15 min of reperfusion.
Results
1. Hemodynamic data includes heart rate ( HR ), LVDP and±dP/dtmax (1) HR: At all time points, there were no significant differences among I/Radult, IPostadult, and IPost+LYadult groups, and no significant differences among the I/Raged, IPostaged, and IPost+LYaged groups. At baseline, I 5 min, R 15 min, R 30 min, the HR of I/Raged group were lower than that of I/Radult group. At all time points, there were no significant differences between IPostadult,and IPostaged , between IPost+LYadult and IPost+LYaged group.
(2) LVDP: At all time points, there were no significant differences among I/Radult, IPostadult, IPost+LYadult groups, and no significant differences among the I/Raged, IPostaged, IPost+LYaged groups. At points of R 5 min, R1 h, and R 2 h, the LVDP of I/Raged group were lower than that of I/Radult group. At points of R 5 min, R 2 h, the LVDP of IPostaged group were lower than that of IPostadult group. At points of R 2 h and R 3 h, the LVDP of IPost+LYaged group were lower than that of IPost+LYadult group.
(3) +dP/dtmax:At R 5 min, R 2 h, and R 3 h, +dP/dtmax of IPostadult were significantly higher than that of I/Radult or IPost+LYadult. But at all time points, there were no significant differences among the I/Raged, IPostaged, IPost+LYaged groups. In the I/Rgroup, there was no significant difference between aged and adult rats. But in the IPost groups, +dP/dtmax of adult rats were significantly higher than that of aged rats during reperfusion except R 1 h. In the IPost+LY groups only at R 30 min +dP/dtmax of adult rats were significantly higher than that of aged rats.
(4) -dP/dtmax: At R2 h, R 3 h, -dP/dtmax of IPostadult were significantly higher than that of I/Radult or IPost+LYadult. But at all time points, there were no significant differences among the I/Raged, IPostaged, IPost+LYaged groups. In the I/R and IPost+LY group, only at I 5 min -dP/dtmax of adult rats were significantly lower than that of aged rats. But in the IPost groups, -dP/dtmax of adult rats were significantly higher than that of aged rats at R 5 min and R 15 min.
2. The area at risk ( in percentage of the left ventricle ) by LAD occlusion was comparable among six groups ( I/Radult, 52.8±5.2% IPostadult, 52.0±5.0% Ipost + LYadult, 52.2±5.8% I/Raged, 51.3±7.2% IPostaged, 53.8±3.5% IPost+LYaged, 51.1±5.8% ). As expected, the postconditioned hearts developed significantly smaller infarct sizes ( expressed as percentage of the area at risk, IS/AAR ) than I/R hearts (11.9±1.6% in IPostadult vs. 30.2±2.8% in I/Radult, P<0.05 13.7±2.5% in IPostaged vs. 27.5±3.5% in I/Raged, P<0.05 ). The PI3K inhibitor, LY294002, abolished IPost’s cardioprotection in aged and adult rats (30.1±2.9% in IPost + LYadult vs. 11.9±1.6% in IPostadult, P<0.05; 33.4±7.0% in IPost + LYaged vs. 13.7±2.5% in IPostaged, P<0.05 ). There were no significant differences between I/Radult and I/Raged, IPostadult and IPostaged, IPost + LYadult and IPost+LYaged. ( all P =NS ).
3. At baseline, the levels of CK in aged groups were lower than that in adult groups, and no differences within aged groups and within adult groups. The levels LDH were no differences between the six groups. Compared with the baseline, CK and LDH release was significantly increased after 3 hours of reperfusion in all I/R, IPost, and IPost+LY groups ( all P < 0.05 vs. baseline ). At 3 h of reperfusion, CK and LDH release in IPost rats was significantly lower than that in I/R groups ( all P< 0.05 vs. I/R groups ). LY294002 prevented the decrease of CK and LDH release in IPost group ( all P<0.05 vs. IPost, not significantly different from I/R groups ).
4. There were no differences in total Akt ( t-Akt ) and total GSK-3β( t-GSK-3β) levels between every two groups. But in both adult and aged rat hearts, IPost significantly increased levels of Akt phosphorylation to levels greater than I/R hearts ( p-Akt/t-Akt: 0.64±0.04 in IPostadult vs. 0.40±0.09 in I/Radult, P<0.05 0.63±0.03 in IPostaged vs. 0.39±0.01 in I/Raged, P<0.05 ). The PI3K inhibitor, LY294002, blocked Akt phosphorylation ( p-Akt/t-Akt: 0.34±0.07 in IPost + LYadult vs. 0.64±0.04 in IPostadult, P<0.05 0.35±0.09 in IPost + LYaged vs. 0.63±0.03 in IPostaged ,P<0.05 ). Similarly, IPost significantly increased levels of GSK-3βphosphorylation to levels greater than I/R hearts, and LY294002 attenuated the levels of phosphorylated-GSK-3βin both adult and aged hearts.
Conclusion
1. Ischemic postconditioning at the onset of reperfusion reduces myocardial infarct size, attenuates the increased levels of CK and LDH, and improve functional preservation after reperfusion in adult SD rats in vivo.
2. An infarct sparing effect for IPost in in vivo heart model of aged rats, which unlike the adult rat model, was not associated with functional preservation.
3. IPost’s cardioprotection in both adult and aged SD rat hearts may be associated with Akt and GSK-3βphosphorylation.
引文
[1] WHO. World health statistics 2007. Geneva: World Health Organization 2007.
[2] WHO. World health statistics 2008. . Geneva: World Health Organization 2008.
[3] Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997 349(9064):1498-1504.
[4] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986 74(5):1124-1136.
[5] Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003 285(2):H579-588.
[6] Zhao ZQ, Vinten-Johansen J. Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res. 2006 70(2):200-211.
[7] Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 357(11):1121-1135.
[8] Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997 349(9063):1436-1442.
[9] Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003 361(9351):13-20.
[10] Verma S, Fedak PW, Weisel RD, Butany J, Rao V, Maitland A, Li RK, Dhillon B, Yau TM. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation. 2002 105(20):2332-2336.
[11] Ames A, 3rd, Wright RL, Kowada M, Thurston JM, Majno G. Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol. 1968 52(2):437-453.
[12] Flores J, DiBona DR, Beck CH, Leaf A. The role of cell swelling in ischemic renal damage and the protective effect of hypertonic solute. J Clin Invest. 1972 51(1):118-126.
[13] Modry DL, Chiu RC. Pulmonary reperfusion syndrome. Ann Thorac Surg. 1979 27(3):206-215.
[14] Tennant R, Wiggers CJ. The effect of coronary occlusion on myocardial contraction. American Journal of Physiology. 1935 112(2):351-361.
[15] Harris AS, Rojas AG. The initiation of ventricular fibrillation due to coronary occlusion. Exp Med Surg 1943(1):105-111.
[16] Sewell WH, Koth DR, Huggins CE. Ventricular fibrillation in dogs after sudden return of flow to the coronary artery. Surgery. 1955 38(6):1050-1053.
[17] Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H. Myocardial necrosisinduced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 1960 70:68-78.
[18] Bulkley BH, Hutchins GM. Accelerated "atherosclerosis". A morphologic study of 97 saphenous vein coronary artery bypass grafts. Circulation. 1977 55(1):163-169.
[19] Hutchins GM, Bulkley BH. Correlation of myocardial contraction band necrosis and vascular patency. A study of coronary artery bypass graft anastomoses at branch points. Lab Invest. 1977 36(6):642-648.
[20] Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med. 2005 15(2):69-75.
[21] Yellon DM, Hausenloy DJ. Realizing the clinical potential of ischemic preconditioning and postconditioning. Nat Clin Pract Cardiovasc Med. 2005 2(11):568-575.
[22] Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res. 2004 62(1):74-85.
[23]高峰, YanWL, YJ G,朱妙章,臧益民,马新亮,蔡振杰.“缺氧后处理”对大鼠缺氧-复氧心室肌细胞的保护作用.心功能杂志. 1999 11(4):241-243.
[24]陶凌,李源,高峰,王跃民,龚卫琴.缺血后处理对急性心肌缺血再灌注兔心脏的保护作用.第四军医大学学报. 2000 21(6):116-118.
[25] Na HS, Kim YI, Yoon YW, Han HC, Nahm SH, Hong SK. Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia. Am Heart J. 1996 132(1 Pt 1):78-83.
[26] Manintveld OC, Te Lintel Hekkert M, van den Bos EJ, Suurenbroek GM, Dekkers DH, Verdouw PD, Lamers JM, Duncker DJ. Cardiac effects of postconditioning depend critically on the duration of index ischemia. Am J Physiol Heart Circ Physiol. 2007 292(3):H1551-1560.
[27] Tang XL, Sato H, Tiwari S, Dawn B, Bi Q, Li Q, Shirk G, Bolli R. Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min. Am J Physiol Heart Circ Physiol. 2006 291(5):H2308-2317.
[28] Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol. 2004 44(5):1103-1110.
[29] Loukogeorgakis SP, Panagiotidou AT, Yellon DM, Deanfield JE, MacAllister RJ. Postconditioning protects against endothelial ischemia-reperfusion injury in the human forearm. Circulation. 2006 113(7):1015-1019.
[30] Ren C, Gao X, Niu G, Yan Z, Chen X, Zhao H. Delayed postconditioning protects against focal ischemic brain injury in rats. PLoS ONE. 2008 3(12):e3851.
[31] Yang XM, Philipp S, Downey JM, Cohen MV. 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 Res Cardiol. 2005 100(1):57-63.
[32] Gritsopoulos G, Iliodromitis EK, Zoga A, Farmakis D, Demerouti E, Papalois A, Paraskevaidis IA, Kremastinos DT. Remote Postconditioning is More Potent than Classic Postconditioning in Reducing the Infarct Size in Anesthetized Rabbits. Cardiovasc Drugs Ther. 2009.
[33] Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 11(1):55-63.
[34] Goodman MD, Koch SE, Fuller-Bicer GA, Butler KL. Regulating RISK: a role for JAK-STAT signaling in postconditioning Am J Physiol Heart Circ Physiol. 2008 295(4):H1649-1656.
[35] Chen HT, Yang CX, Li H, Zhang CJ, Wen XJ, Zhou J, Fan YL, Huang T, Zeng YM. Cardioprotection of sevoflurane postconditioning by activating extracellular signal-regulated kinase 1/2 in isolated rat hearts. Acta Pharmacol Sin. 2008 29(8):931-941.
[36] Nishida H, Sato T, Nomura M, Miyazaki M, Nakaya H. Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts. J Pharmacol Sci. 2009 109(2):251-256.
[37] Hu X, Jiang H, Ma F, Xu C, Bo C, Wen H, Wu B, Lu Z. Similarities between ischemic preconditioning and postconditioning in myocardial ischemia/reperfusion injury. Int J Cardiol. 2009.
[38] Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G. Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res. 2009 104(1):15-18.
[39] Zhang YM, Wang Y, Liu XH, Zhang DW. [Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/reperfusion injury: experiment with rats]. Zhonghua Yi Xue Za Zhi. 2008 88(36):2558-2561.
[40] Bouhidel O, Pons S, Souktani R, Zini R, Berdeaux A, Ghaleh B. Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol. 2008 295(4):H1580-1586.
[41] Mykytenko J, Reeves JG, Kin H, Wang NP, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ. Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial K(ATP) channels during reperfusion. Basic Res Cardiol. 2008 103(5):472-484.
[42] Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation.2005 111(2):194-197.
[43] Zhu M, Feng J, Lucchinetti E, Fischer G, Xu L, Pedrazzini T, Schaub MC, Zaugg M. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res. 2006 72(1):152-162.
[44] Zhao JL, Yang YJ, You SJ, Cui CJ, Gao RL. Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc Res. 2007 73(2):137-142.
[45] Wagner C, Kloeting I, Strasser RH, Weinbrenner C. Cardioprotection by postconditioning is lost in WOKW rats with metabolic syndrome: role of glycogen synthase kinase 3beta. J Cardiovasc Pharmacol. 2008 52(5):430-437.
[46] Crisostomo PR, Wang M, Wairiuko GM, Terrell AM, Meldrum DR. Postconditioning in females depends on injury severity. J Surg Res. 2006 134(2):342-347.
[47] Penna C, Tullio F, Merlino A, Moro F, Raimondo S, Rastaldo R, Perrelli MG, Mancardi D, Pagliaro P. Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender. Basic Res Cardiol. 2008.
[48] Lauzier B, Delemasure S, Debin R, Collin B, Sicard P, Acar N, Bretillon L, Joffre C, Bron A, Creuzot-Garcher C, Vergely C, Rochette L. Beneficial effects of myocardial postconditioning are associated with reduced oxidative stress in a senescent mouse model. Transplantation. 2008 85(12):1802-1808.
[49]范谦,杨新春,王树岩,陈瑾,迟洪杰,刘胜辉.“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(4):363-366.
[50] Kerendi F, Kin H, Halkos ME, Jiang R, Zatta AJ, Zhao ZQ, Guyton RA, Vinten-Johansen J. 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(5):404-412.
[51]张兴华,李春梅,马晓静,罗曼.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究.中华医学杂志. 2006 86(12):841-845.
[52] Zhang XH, Li CM, Ma XJ, Luo M. [Correlation of limb and myocardial ischemia postconditioning with acute myocardial reperfusion injury]. Zhonghua Yi Xue Za Zhi. 2006 86(12):841-845.
[53] Andreadou I, Iliodromitis EK, Koufaki M, Kremastinos DT. Pharmacological pre- and post- conditioning agents: reperfusion-injury of the heart revisited. Mini Rev Med Chem. 2008 8(9):952-959.
[54] Kin H, Zatta AJ, Lofye MT, Amerson BS, Halkos ME, Kerendi F, Zhao ZQ, Guyton RA, Headrick JP, Vinten-Johansen J. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res. 2005 67(1):124-133.
[55] Lu J, Zang WJ, Yu XJ, Jia B, Chorvatova A, Sun L. Effects of postconditioning ofadenosine and acetylcholine on the ischemic isolated rat ventricular myocytes. Eur J Pharmacol. 2006 549(1-3):133-139.
[56] Zang WJ, Sun L, Yu XJ. Cardioprotection of ischemic postconditioning and pharmacological post-treatment with adenosine or acetylcholine. Sheng Li Xue Bao. 2007 59(5):593-600.
[57] Cserepes B, Jancso G, Gasz B, Racz B, Ferenc A, Benko L, Borsiczky B, Kurthy M, Ferencz S, Lantos J, Gal J, Arato E, Miseta A, Weber G, Roth E. Cardioprotective action of urocortin in early pre- and postconditioning. Ann N Y Acad Sci. 2007 1095:228-239.
[58] Zhang HX, Zang YM, Huo JH, Liang SJ, Zhang HF, Wang YM, Fan Q, Guo WY, Wang HC, Gao F. Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs. J Cardiovasc Pharmacol. 2006 48(6):306-313.
[59] Tissier R, Waintraub X, Couvreur N, Gervais M, Bruneval P, Mandet C, Zini R, Enriquez B, Berdeaux A, Ghaleh B. Pharmacological postconditioning with the phytoestrogen genistein. J Mol Cell Cardiol. 2007 42(1):79-87.
[60] Lucchinetti E, da Silva R, Pasch T, Schaub M, Zaugg M. Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning. Br J Anaesth. 2005 95(2):140-152.
[61] Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg. 2005 101(5):1252-1260.
[62] Feng J, Lucchinetti E, Ahuja P, Pasch T, Perriard JC, Zaugg M. Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology. 2005 103(5):987-995.
[63] Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology. 2005 102(1):102-109.
[64] Karliner JS. Sphingosine Kinase and Sphingosine 1-Phosphate in Cardioprotection. J Cardiovasc Pharmacol. 2009.
[65] Sicard P, Jacquet S, Kobayashi KS, Flavell RA, Marber MS. Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1. Cardiovasc Res. 2009.
[66] Burley DS, Baxter GF. B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. Basic Res Cardiol. 2007 102(6):529-541.
[67] Lemoine S, Beauchef G, Zhu L, Renard E, Lepage O, Massetti M, Khayat A, Galera P, Gerard JL, Hanouz JL. Signaling pathways involved in desflurane-induced postconditioning in human atrial myocardium in vitro. Anesthesiology. 2008 109(6):1036-1044.
[68] Fang J, Wu L, Chen L. Postconditioning attenuates cardiocyte ultrastructure injury and apoptosis by blocking mitochondrial permeability transition in rats. Acta Cardiol. 2008 63(3):377-387.
[69] Baxter GF, Burley DS. Reperfusion and calculated RISKs: pharmacological postconditioning of human myocardium. Br J Pharmacol. 2008 153(1):1-3.
[70] Zatta AJ, Kin H, Yoshishige D, Jiang R, Wang N, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Caffrey JL, Vinten-Johansen J. Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation. Am J Physiol Heart Circ Physiol. 2008 294(3):H1444-1451.
[71] Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J Surg Res. 2008 145(2):287-294.
[72] Ji Y, Pang QF, Xu G, Wang L, Wang JK, Zeng YM. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J Pharmacol. 2008 587(1-3):1-7.
[73] Murozono Y, Takahashi N, Shinohara T, Ooie T, Teshima Y, Hara M, Saikawa T, Yoshimatsu H. Hyperthermia-Induced Cardioprotection Is Potentiated by Ischemic Postconditioning in Rats. Exp Biol Med (Maywood). 2009.
[74] Luo W, Li B, Chen R, Huang R, Lin G. Effect of ischemic postconditioning in adult valve replacement. Eur J Cardiothorac Surg. 2008 33(2):203-208.
[75] Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary intervention for acute myocardial infarction: a benefit of postconditioning. Catheter Cardiovasc Interv. 2008 72(2):212-220.
[76] Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M. Postconditioning the human heart. Circulation. 2005 112(14):2143-2148.
[77] Ma X, Zhang X, Li C, Luo M. Effect of postconditioning on coronary blood flow velocity and endothelial function and LV recovery after myocardial infarction. J Interv Cardiol. 2006 19(5):367-375.
[78] Darling CE, Jiang R, Maynard M, Whittaker P, Vinten-Johansen J, Przyklenk K. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2. Am J Physiol Heart Circ Physiol. 2005 289(4):H1618-1626.
[79] Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM. Postconditioning: a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res. 2004 95(3):230-232.
[80] Galagudza M, Kurapeev D, Minasian S, Valen G, Vaage J. Ischemic postconditioning: brief ischemia during reperfusion converts persistent ventricular fibrillation into regular rhythm. Eur J Cardiothorac Surg. 2004 25(6):1006-1010.
[81] Halkos ME, Kerendi F, Corvera JS, Wang NP, Kin H, Payne CS, Sun HY, Guyton RA, Vinten-Johansen J, Zhao ZQ. Myocardial protection with postconditioning is not enhanced by ischemic preconditioning. Ann Thorac Surg. 2004 78(3):961-969 discussion 969.
[82] Dow J, Bhandari A, Kloner RA. Ischemic postconditioning's benefit on reperfusion ventricular arrhythmias is maintained in the senescent heart. J Cardiovasc Pharmacol Ther. 2008 13(2):141-148.
[83] Dragoni S, Di Stolfo G, Sicuro S, Lisi M, Parker JD, Forconi S, Gori T. Postconditioning fails to prevent radial artery endothelial dysfunction induced by ischemia and reperfusion: evidence from a human in vivo study. Can J Physiol Pharmacol. 2006 84(6):611-615.
[84] Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003 60(3):617-625.
[85] Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res. 2006 69(1):178-185.
[86] Lim SY, Davidson SM, Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovasc Res. 2007 75(3):530-535.
[87] Liu XH, Zhang ZY, Sun S, Wu XD. Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock. 2008 30(4):422-427.
[88] Rey FE, Li XC, Carretero OA, Garvin JL, Pagano PJ. Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation: role of gp91(phox). Circulation. 2002 106(19):2497-2502.
[89] Bolli R, Patel BS, Jeroudi MO, Lai EK, McCay PB. Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone. J Clin Invest. 1988 82(2):476-485.
[90] Sun HY, Wang NP, Kerendi F, Halkos M, Kin H, Guyton RA, Vinten-Johansen J, Zhao ZQ. Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+ overload. Am J Physiol Heart Circ Physiol. 2005 288(4):H1900-1908.
[91] Sun K, Liu ZS, Sun Q. Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning. World J Gastroenterol. 2004 10(13):1934-1938.
[92] Petrishchev NN, Vlasov TD, Galagudza MM, Kurapeev DI, Minasian SM. [Myocardial ischemic postconditioning: a brief ischemia causes conversion of resistent reperfusion-induced ventricular fibrillation into the normal rhythm]. Ross Fiziol Zh Im I M Sechenova. 2004 90(9):1138-1144.
[93]刘秀华,唐朝枢.缺血再灌注损伤的防治——从实验室到临床.中华心血管病杂志. 2006 34(8):677-679.
[94] Zhao Z, Zang Y. Alternative cardioprotective strategy during reperfusion:postconditioning vs preconditioning [J]. Chin Heart J 2006 18(1):1-7, 13.
[95] Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res. 2006 70(2):308-314.
[96]王珏,高琴,沈佳,叶挺梅,夏强.阿片受体介导缺血后处理的心肌保护作用及其受体后机制. .浙江大学学报(医学版) 2007 36(1):7.
[97] Ventura C, Spurgeon H, Lakatta EG, Guarnieri C, Capogrossi MC. Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. Circ Res. 1992 70(1):66-81.
[98] Xiao RP, Pepe S, Spurgeon HA, Capogrossi MC, Lakatta EG. Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells. Am J Physiol. 1997 272(2 Pt 2):H797-805.
[99] Kin H, Zatta AJ, Jiang R. Activation of opioid receptors mediates the infarct postconditioning. J Mol Cell Cardiol. 2005 38(5):827.
[100] Gross ER, Gross GJ. Ligand triggers of classical preconditioning and postconditioning. Cardiovasc Res. 2006 70(2):212-221.
[101] Ping P, Zhang J, Cao X, Li RC, Kong D, Tang XL, Qiu Y, Manchikalapudi S, Auchampach JA, Black RG, Bolli R. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol. 1999 276(5 Pt 2):H1468-1481.
[102] Fantinelli JC, Mosca SM. Comparative effects of ischemic pre and postconditioning on ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Mol Cell Biochem. 2007 296(1-2):45-51.
[103] Zatta AJ, Kin H, Lee G, Wang N, Jiang R, Lust R, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Vinten-Johansen J. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling. Cardiovasc Res. 2006 70(2):315-324.
[104]孙胜,高钰琪,高文祥,范明.缺氧诱导因子1与PI3K/Akt/mTOR信号转导通路.生命科学. 2005 17(4):311-314.
[105] Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002 296(5573):1655-1657.
[106] Fujita M, Asanuma H, Hirata A, Wakeno M, Takahama H, Sasaki H, Kim J, Takashima S, Tsukamoto O, Minamino T, Shinozaki Y, Tomoike H, Hori M, Kitakaze M.Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning. Am J Physiol Heart Circ Physiol. 2007 292(4):H2004-2008.
[107] Schwartz LM, Lagranha CJ. Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs. Am J Physiol Heart Circ Physiol. 2006 290(3):H1011-1018.
[108] Burley DS, Ferdinandy P, Baxter GF. Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. Br J Pharmacol. 2007 152(6):855-869.
[109] Cohen MV, Downey JM. Cardioprotection: spotlight on PKG. Br J Pharmacol. 2007 152(6):833-834.
[110] Takuma K, Phuagphong P, Lee E, Mori K, Baba A, Matsuda T. Anti-apoptotic effect of cGMP in cultured astrocytes: inhibition by cGMP-dependent protein kinase of mitochondrial permeable transition pore. J Biol Chem. 2001 276(51):48093-48099.
[111]刘秀华,苏静怡.缺血预处理的研究现状.生理科学进展. 2001 32(1):83-87.
[112]祝筱梅,刘秀华,蔡莉蓉,徐菲菲. p38丝裂素活化蛋白激酶介导低氧预处理诱导的内质网应激相关的心肌细胞保护.生理学报. 2006 58(5):463-470.
[113] Hausenloy DJ, Yellon DM. Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res. 2006 70(2):240-253.
[114] Sun HY, Wang NP, Halkos M, Kerendi F, Kin H, Guyton RA, Vinten-Johansen J, Zhao ZQ. Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis. 2006 11(9):1583-1593.
[115]祝筱梅,刘秀华,蔡莉蓉.缺氧后处理对缺氧/复氧心肌细胞的保护作用及其机理研究.中国微循环. 2007 11(4):223-230.
[116] Kaiser RA, Liang Q, Bueno O, Huang Y, Lackey T, Klevitsky R, Hewett TE, Molkentin JD. Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo. J Biol Chem. 2005 280(38):32602-32608.
[117] Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. Cardiovasc Res. 2004 61(3):372-385.
[118] Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J. 1995 307 ( Pt 1):93-98.
[119] Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning Cardiovasc Res. 2002 55(3):534-543.
[120] Gomez L, Chavanis N, Argaud L, Chalabreysse L, Gateau-Roesch O, Ninet J, Ovize M. Fas-independent mitochondrial damage triggers cardiomyocyte death afterischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2005 289(5):H2153-2158.
[121] Irie H, Gao J, Gaudette GR, Cohen IS, Mathias RT, Saltman AE, Krukenkamp IB. Both metabolic inhibition and mitochondrial K(ATP) channel opening are myoprotective and initiate a compensatory sarcolemmal outward membrane current. Circulation. 2003 108 Suppl 1:II341-347.
[122] Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliaro P. Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol. 2006 101(2):180-189.
[123] Koseki T, Inohara N, Chen S, Nunez G. ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci U S A. 1998 95(9):5156-5160.
[124] Li YZ, Liu XH, Zhu XM, Cai LR. ARC contributes to the inhibitory effect of preconditioning on cardiomyocyte apoptosis. Apoptosis. 2007 12(9):1589-1595.
[125] Wu ZK, Pehkonen E, Laurikka J, Kaukinen L, Honkonen EL, Kaukinen S, Laippala P, Tarkka MR. The protective effects of preconditioning decline in aged patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2001 122(5):972-978.
[126] Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol. 2006 47(11):2277-2282.
[127] Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F. Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2005 100(4):295-310.
[128]祝筱梅,刘秀华.缺血-再灌注损伤防治的新方法——缺血后处理的研究现状.生理科学进展. 2007 38(3):261-265.
[129] Iliodromitis EK, Zoga A, Vrettou A, Andreadou I, Paraskevaidis IA, Kaklamanis L, Kremastinos DT. The effectiveness of postconditioning and preconditioning on infarct size in hypercholesterolemic and normal anesthetized rabbits. Atherosclerosis. 2006 188(2):356-362.
[130] Mykytenko J, Kerendi F, Reeves JG, Kin H, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ. Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol. 2007 102(1):90-100.
[131] Downey JM, Cohen MV. We think we see a pattern emerging here. Circulation. 2005 111(2):120-121.
[132] Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol.2005 288(2):H971-976.
[133] Laskey WK. Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study. Catheter Cardiovasc Interv. 2005 65(3):361-367.
[134] Guo Y, Wu WJ, Qiu Y, Tang XL, Yang Z, Bolli R. Demonstration of an early and a late phase of ischemic preconditioning in mice. Am J Physiol. 1998 275(4 Pt 2):H1375-1387.
[135] Wang G, Liem DA, Vondriska TM, Honda HM, Korge P, Pantaleon DM, Qiao X, Wang Y, Weiss JN, Ping P. Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition. Am J Physiol Heart Circ Physiol. 2005 288(3):H1290-1295.
[136] Klein HH PS, Schaper J, Schaper W. The mechanism of the tetrazolium reaction in identifying experimental myocardial infarction. Virchows Arch. 1981(393):287-297.
[137] Schwarz ER, Somoano Y, Hale SL, Kloner RA. What is the required reperfusion period for assessment of myocardial infarct size using triphenyltetrazolium chloride staining in the rat J Thromb Thrombolysis. 2000 10(2):181-187.
[138] Goto M, Tsuchida A, Liu Y, Cohen MV, Downey JM. Transient inhibition of glucose uptake mimics ischemic preconditioning by salvaging ischemic myocardium in the rabbit heart. J Mol Cell Cardiol. 1995 27(9):1883-1894.
[139] Sack S, Mohri M, Arras M, Schwarz ER, Schaper W. Ischaemic preconditioning--time course of renewal in the pig. Cardiovasc Res. 1993 27(4):551-555.
[140] Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol. 1995 268(5 Pt 2):H2157-2161.
[141] Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996 94(9):2193-2200.
[142] Michael LH, Entman ML, Hartley CJ, Youker KA, Zhu J, Hall SR, Hawkins HK, Berens K, Ballantyne CM. Myocardial ischemia and reperfusion: a murine model. Am J Physiol. 1995 269(6 Pt 2):H2147-2154.
[143] Birnbaum Y, Hale SL, Kloner RA. Differences in reperfusion length following 30 minutes of ischemia in the rabbit influence infarct size, as measured by triphenyltetrazolium chloride staining. J Mol Cell Cardiol. 1997 29(2):657-666.
[144] Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003 92(8):873-880.
[145] Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res. 2008 102(1):131-135.
[146] Iliodromitis EK, Georgiadis M, Cohen MV, Downey JM, Bofilis E, Kremastinos DT. Protection from post-conditioning depends on the number of short ischemic insults inanesthetized pigs. Basic Res Cardiol. 2006 101(6):502-507.
[147] Liu P, Xu B, Cavalieri TA, Hock CE. Age-related difference in myocardial function and inflammation in a rat model of myocardial ischemia-reperfusion. Cardiovasc Res. 2002 56(3):443-453.
[148] Oudot A, Martin C, Busseuil D, Vergely C, Demaison L, Rochette L. NADPH oxidases are in part responsible for increased cardiovascular superoxide production during aging. Free Radic Biol Med. 2006 40(12):2214-2222.
[149] Fenton RA, Dickson EW, Dobson JG, Jr. Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart. Life Sci. 2005 77(26):3375-3388.
[150] Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol. 2005 39(2):285-296.
[151] Crews DE. Artificial environments and an aging population: designing for age-related functional losses. J Physiol Anthropol Appl Human Sci. 2005 24(1):103-109.
[152] Pahor M, Di Gennaro M, Cocchi A, Bernabei R, Carosella L, Carbonin P. Age-related incidence of reperfusion- and reoxygenation-induced ventricular tachyarrhythmias in the isolated rat heart. Gerontology. 1985 31(1):15-26.
[153] Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Cacciatore F, Longobardi G, Rengo F. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol. 1996 27(7):1777-1786.
[154] Boucher F, Tanguy S, Besse S, Tresallet N, Favier A, de Leiris J. Age-dependent changes in myocardial susceptibility to zero flow ischemia and reperfusion in isolated perfused rat hearts: relation to antioxidant status. Mech Ageing Dev. 1998 103(3):301-316.
[155] Headrick JP. Aging impairs functional, metabolic and ionic recovery from ischemia-reperfusion and hypoxia-reoxygenation. J Mol Cell Cardiol. 1998 30(7):1415-1430.
[156] Cain BS, Meldrum DR, Joo KS, Wang JF, Meng X, Cleveland JC, Jr., Banerjee A, Harken AH. Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol. 1998 32(2):458-467.
[157] Lim CC, Liao R, Varma N, Apstein CS. Impaired lusitropy-frequency in the aging mouse: role of Ca(2+)-handling proteins and effects of isoproterenol. Am J Physiol. 1999 277(5 Pt 2):H2083-2090.
[158] Nitahara JA, Cheng W, Liu Y, Li B, Leri A, Li P, Mogul D, Gambert SR, Kajstura J, Anversa P. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats. J Mol Cell Cardiol. 1998 30(3):519-535.
[159] Abete P, Napoli C, Santoro G, Ferrara N, Tritto I, Chiariello M, Rengo F, Ambrosio G. Age-related decrease in cardiac tolerance to oxidative stress. J Mol Cell Cardiol.1999 31(1):227-236.
[160] Pepe S. Mitochondrial function in ischaemia and reperfusion of the ageing heart. Clin Exp Pharmacol Physiol. 2000 27(9):745-750.
[161] Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001 33(6):1065-1089.
[162] Higami Y, Shimokawa I. Apoptosis in the aging process. Cell Tissue Res. 2000 301(1):125-132.
[163] Phaneuf S, Leeuwenburgh C. Cytochrome c release from mitochondria in the aging heart: a possible mechanism for apoptosis with age. Am J Physiol Regul Integr Comp Physiol. 2002 282(2):R423-430.
[164] Ungvari Z, Csiszar A, Kaley G. Vascular inflammation in aging. Herz. 2004 29(8):733-740.
[165] Betsuyaku T, Kovacs A, Saffitz JE, Yamada KA. Cardiac structure and function in young and senescent mice heterozygous for a connexin43 null mutation. J Mol Cell Cardiol. 2002 34(2):175-184.
[166] Olsson MC, Palmer BM, Leinwand LA, Moore RL. Gender and aging in a transgenic mouse model of hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2001 280(3):H1136-1144.
[167] Heusch G, Buchert A, Feldhaus S, Schulz R. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic Res Cardiol. 2006 101(4):354-356.
[168] Dow J, Kloner RA. Postconditioning does not reduce myocardial infarct size in an in vivo regional ischemia rodent model. J Cardiovasc Pharmacol Ther. 2007 12(2):153-163.
[169] Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol. 2008 51(14):1393-1398.
[170] Fenton RA, Dickson EW, Meyer TE, Dobson JG, Jr. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol. 2000 32(7):1371-1375.
[171] Burns PG, Krunkenkamp IB, Calderone CA, Kirvaitis RJ, Gaudette GR, Levitsky S. Is the preconditioning response conserved in senescent myocardium Ann Thorac Surg. 1996 61(3):925-929.
[172] Krieg T, Qin Q, McIntosh EC, Cohen MV, Downey JM. ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases. Am J Physiol Heart Circ Physiol. 2002 283(6):H2322-2330.
[173] Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004 30(2):193-204.
[174] Martineau LC, Chadan SG, Parkhouse WS. Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse. Mech Ageing Dev. 1999 106(3):217-232.
[175] Centurione L, Antonucci A, Miscia S, Grilli A, Rapino M, Grifone G, Di Giacomo V, Di Giulio C, Falconi M, Cataldi A. Age-related death-survival balance in myocardium: an immunohistochemical and biochemical study. Mech Ageing Dev. 2002 123(4):341-350.
[176] Abete P, Testa G, Ferrara N, De Santis D, Capaccio P, Viati L, Calabrese C, Cacciatore F, Longobardi G, Condorelli M, Napoli C, Rengo F. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats. Am J Physiol Heart Circ Physiol. 2002 282(6):H1978-1987.
[177] Steinbrecher KA, Wilson W, 3rd, Cogswell PC, Baldwin AS. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Mol Cell Biol. 2005 25(19):8444-8455.
[178] Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res. 2002 90(4):377-379.
[179] Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH. Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 2001 105(6):721-732.
[180] Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004 113(11):1535-1549.
[181] van Weeren PC, de Bruyn KM, de Vries-Smits AM, van Lint J, Burgering BM. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB. J Biol Chem. 1998 273(21):13150-13156.
[182] Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999 401(6748):82-85.
[183] Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation. 2001 104(3):330-335.
[184] Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem. 1998 273(32):19929-19932.
[185] Murphy E, Steenbergen C. Inhibition of GSK-3beta as a target for cardioprotection: the importance of timing, location, duration and degree of inhibition. Expert Opin Ther Targets. 2005 9(3):447-456.
[186] Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res. 2000 87(4):309-315.
[187] Pagel PS, Krolikowski JG, Neff DA, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC. Inhibition of glycogen synthase kinase enhances isoflurane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg. 2006 102(5):1348-1354.
[188] Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 268(20):14553-14556.
[189] Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004 61(3):448-460.
[190] Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC, Pagel PS. Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anaesth. 2006 53(2):174-182.
[191] Peart JN, Gross GJ. Chronic exposure to morphine produces a marked cardioprotective phenotype in aged mouse hearts. Exp Gerontol. 2004 39(7):1021-1026.
[192] Bartling B, Friedrich I, Silber RE, Simm A. Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg. 2003 76(1):105-111.
[2] WHO. World health statistics 2008. . Geneva: World Health Organization 2008.
[3] Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997 349(9064):1498-1504.
[4] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986 74(5):1124-1136.
[5] Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003 285(2):H579-588.
[6] Zhao ZQ, Vinten-Johansen J. Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res. 2006 70(2):200-211.
[7] Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 357(11):1121-1135.
[8] Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997 349(9063):1436-1442.
[9] Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003 361(9351):13-20.
[10] Verma S, Fedak PW, Weisel RD, Butany J, Rao V, Maitland A, Li RK, Dhillon B, Yau TM. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation. 2002 105(20):2332-2336.
[11] Ames A, 3rd, Wright RL, Kowada M, Thurston JM, Majno G. Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol. 1968 52(2):437-453.
[12] Flores J, DiBona DR, Beck CH, Leaf A. The role of cell swelling in ischemic renal damage and the protective effect of hypertonic solute. J Clin Invest. 1972 51(1):118-126.
[13] Modry DL, Chiu RC. Pulmonary reperfusion syndrome. Ann Thorac Surg. 1979 27(3):206-215.
[14] Tennant R, Wiggers CJ. The effect of coronary occlusion on myocardial contraction. American Journal of Physiology. 1935 112(2):351-361.
[15] Harris AS, Rojas AG. The initiation of ventricular fibrillation due to coronary occlusion. Exp Med Surg 1943(1):105-111.
[16] Sewell WH, Koth DR, Huggins CE. Ventricular fibrillation in dogs after sudden return of flow to the coronary artery. Surgery. 1955 38(6):1050-1053.
[17] Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H. Myocardial necrosisinduced by temporary occlusion of a coronary artery in the dog. Arch Pathol. 1960 70:68-78.
[18] Bulkley BH, Hutchins GM. Accelerated "atherosclerosis". A morphologic study of 97 saphenous vein coronary artery bypass grafts. Circulation. 1977 55(1):163-169.
[19] Hutchins GM, Bulkley BH. Correlation of myocardial contraction band necrosis and vascular patency. A study of coronary artery bypass graft anastomoses at branch points. Lab Invest. 1977 36(6):642-648.
[20] Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med. 2005 15(2):69-75.
[21] Yellon DM, Hausenloy DJ. Realizing the clinical potential of ischemic preconditioning and postconditioning. Nat Clin Pract Cardiovasc Med. 2005 2(11):568-575.
[22] Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res. 2004 62(1):74-85.
[23]高峰, YanWL, YJ G,朱妙章,臧益民,马新亮,蔡振杰.“缺氧后处理”对大鼠缺氧-复氧心室肌细胞的保护作用.心功能杂志. 1999 11(4):241-243.
[24]陶凌,李源,高峰,王跃民,龚卫琴.缺血后处理对急性心肌缺血再灌注兔心脏的保护作用.第四军医大学学报. 2000 21(6):116-118.
[25] Na HS, Kim YI, Yoon YW, Han HC, Nahm SH, Hong SK. Ventricular premature beat-driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia. Am Heart J. 1996 132(1 Pt 1):78-83.
[26] Manintveld OC, Te Lintel Hekkert M, van den Bos EJ, Suurenbroek GM, Dekkers DH, Verdouw PD, Lamers JM, Duncker DJ. Cardiac effects of postconditioning depend critically on the duration of index ischemia. Am J Physiol Heart Circ Physiol. 2007 292(3):H1551-1560.
[27] Tang XL, Sato H, Tiwari S, Dawn B, Bi Q, Li Q, Shirk G, Bolli R. Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min. Am J Physiol Heart Circ Physiol. 2006 291(5):H2308-2317.
[28] Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol. 2004 44(5):1103-1110.
[29] Loukogeorgakis SP, Panagiotidou AT, Yellon DM, Deanfield JE, MacAllister RJ. Postconditioning protects against endothelial ischemia-reperfusion injury in the human forearm. Circulation. 2006 113(7):1015-1019.
[30] Ren C, Gao X, Niu G, Yan Z, Chen X, Zhao H. Delayed postconditioning protects against focal ischemic brain injury in rats. PLoS ONE. 2008 3(12):e3851.
[31] Yang XM, Philipp S, Downey JM, Cohen MV. 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 Res Cardiol. 2005 100(1):57-63.
[32] Gritsopoulos G, Iliodromitis EK, Zoga A, Farmakis D, Demerouti E, Papalois A, Paraskevaidis IA, Kremastinos DT. Remote Postconditioning is More Potent than Classic Postconditioning in Reducing the Infarct Size in Anesthetized Rabbits. Cardiovasc Drugs Ther. 2009.
[33] Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 11(1):55-63.
[34] Goodman MD, Koch SE, Fuller-Bicer GA, Butler KL. Regulating RISK: a role for JAK-STAT signaling in postconditioning Am J Physiol Heart Circ Physiol. 2008 295(4):H1649-1656.
[35] Chen HT, Yang CX, Li H, Zhang CJ, Wen XJ, Zhou J, Fan YL, Huang T, Zeng YM. Cardioprotection of sevoflurane postconditioning by activating extracellular signal-regulated kinase 1/2 in isolated rat hearts. Acta Pharmacol Sin. 2008 29(8):931-941.
[36] Nishida H, Sato T, Nomura M, Miyazaki M, Nakaya H. Glimepiride Treatment Upon Reperfusion Limits Infarct Size via the Phosphatidylinositol 3-Kinase/Akt Pathway in Rabbit Hearts. J Pharmacol Sci. 2009 109(2):251-256.
[37] Hu X, Jiang H, Ma F, Xu C, Bo C, Wen H, Wu B, Lu Z. Similarities between ischemic preconditioning and postconditioning in myocardial ischemia/reperfusion injury. Int J Cardiol. 2009.
[38] Skyschally A, van Caster P, Boengler K, Gres P, Musiolik J, Schilawa D, Schulz R, Heusch G. Ischemic postconditioning in pigs: no causal role for RISK activation. Circ Res. 2009 104(1):15-18.
[39] Zhang YM, Wang Y, Liu XH, Zhang DW. [Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/reperfusion injury: experiment with rats]. Zhonghua Yi Xue Za Zhi. 2008 88(36):2558-2561.
[40] Bouhidel O, Pons S, Souktani R, Zini R, Berdeaux A, Ghaleh B. Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice. Am J Physiol Heart Circ Physiol. 2008 295(4):H1580-1586.
[41] Mykytenko J, Reeves JG, Kin H, Wang NP, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ. Persistent beneficial effect of postconditioning against infarct size: role of mitochondrial K(ATP) channels during reperfusion. Basic Res Cardiol. 2008 103(5):472-484.
[42] Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation.2005 111(2):194-197.
[43] Zhu M, Feng J, Lucchinetti E, Fischer G, Xu L, Pedrazzini T, Schaub MC, Zaugg M. Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res. 2006 72(1):152-162.
[44] Zhao JL, Yang YJ, You SJ, Cui CJ, Gao RL. Different effects of postconditioning on myocardial no-reflow in the normal and hypercholesterolemic mini-swines. Microvasc Res. 2007 73(2):137-142.
[45] Wagner C, Kloeting I, Strasser RH, Weinbrenner C. Cardioprotection by postconditioning is lost in WOKW rats with metabolic syndrome: role of glycogen synthase kinase 3beta. J Cardiovasc Pharmacol. 2008 52(5):430-437.
[46] Crisostomo PR, Wang M, Wairiuko GM, Terrell AM, Meldrum DR. Postconditioning in females depends on injury severity. J Surg Res. 2006 134(2):342-347.
[47] Penna C, Tullio F, Merlino A, Moro F, Raimondo S, Rastaldo R, Perrelli MG, Mancardi D, Pagliaro P. Postconditioning cardioprotection against infarct size and post-ischemic systolic dysfunction is influenced by gender. Basic Res Cardiol. 2008.
[48] Lauzier B, Delemasure S, Debin R, Collin B, Sicard P, Acar N, Bretillon L, Joffre C, Bron A, Creuzot-Garcher C, Vergely C, Rochette L. Beneficial effects of myocardial postconditioning are associated with reduced oxidative stress in a senescent mouse model. Transplantation. 2008 85(12):1802-1808.
[49]范谦,杨新春,王树岩,陈瑾,迟洪杰,刘胜辉.“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(4):363-366.
[50] Kerendi F, Kin H, Halkos ME, Jiang R, Zatta AJ, Zhao ZQ, Guyton RA, Vinten-Johansen J. 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(5):404-412.
[51]张兴华,李春梅,马晓静,罗曼.肢体与心肌缺血后处理对兔急性心肌缺血再灌注损伤的对比研究.中华医学杂志. 2006 86(12):841-845.
[52] Zhang XH, Li CM, Ma XJ, Luo M. [Correlation of limb and myocardial ischemia postconditioning with acute myocardial reperfusion injury]. Zhonghua Yi Xue Za Zhi. 2006 86(12):841-845.
[53] Andreadou I, Iliodromitis EK, Koufaki M, Kremastinos DT. Pharmacological pre- and post- conditioning agents: reperfusion-injury of the heart revisited. Mini Rev Med Chem. 2008 8(9):952-959.
[54] Kin H, Zatta AJ, Lofye MT, Amerson BS, Halkos ME, Kerendi F, Zhao ZQ, Guyton RA, Headrick JP, Vinten-Johansen J. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res. 2005 67(1):124-133.
[55] Lu J, Zang WJ, Yu XJ, Jia B, Chorvatova A, Sun L. Effects of postconditioning ofadenosine and acetylcholine on the ischemic isolated rat ventricular myocytes. Eur J Pharmacol. 2006 549(1-3):133-139.
[56] Zang WJ, Sun L, Yu XJ. Cardioprotection of ischemic postconditioning and pharmacological post-treatment with adenosine or acetylcholine. Sheng Li Xue Bao. 2007 59(5):593-600.
[57] Cserepes B, Jancso G, Gasz B, Racz B, Ferenc A, Benko L, Borsiczky B, Kurthy M, Ferencz S, Lantos J, Gal J, Arato E, Miseta A, Weber G, Roth E. Cardioprotective action of urocortin in early pre- and postconditioning. Ann N Y Acad Sci. 2007 1095:228-239.
[58] Zhang HX, Zang YM, Huo JH, Liang SJ, Zhang HF, Wang YM, Fan Q, Guo WY, Wang HC, Gao F. Physiologically tolerable insulin reduces myocardial injury and improves cardiac functional recovery in myocardial ischemic/reperfused dogs. J Cardiovasc Pharmacol. 2006 48(6):306-313.
[59] Tissier R, Waintraub X, Couvreur N, Gervais M, Bruneval P, Mandet C, Zini R, Enriquez B, Berdeaux A, Ghaleh B. Pharmacological postconditioning with the phytoestrogen genistein. J Mol Cell Cardiol. 2007 42(1):79-87.
[60] Lucchinetti E, da Silva R, Pasch T, Schaub M, Zaugg M. Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning. Br J Anaesth. 2005 95(2):140-152.
[61] Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg. 2005 101(5):1252-1260.
[62] Feng J, Lucchinetti E, Ahuja P, Pasch T, Perriard JC, Zaugg M. Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology. 2005 103(5):987-995.
[63] Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology. 2005 102(1):102-109.
[64] Karliner JS. Sphingosine Kinase and Sphingosine 1-Phosphate in Cardioprotection. J Cardiovasc Pharmacol. 2009.
[65] Sicard P, Jacquet S, Kobayashi KS, Flavell RA, Marber MS. Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1. Cardiovasc Res. 2009.
[66] Burley DS, Baxter GF. B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. Basic Res Cardiol. 2007 102(6):529-541.
[67] Lemoine S, Beauchef G, Zhu L, Renard E, Lepage O, Massetti M, Khayat A, Galera P, Gerard JL, Hanouz JL. Signaling pathways involved in desflurane-induced postconditioning in human atrial myocardium in vitro. Anesthesiology. 2008 109(6):1036-1044.
[68] Fang J, Wu L, Chen L. Postconditioning attenuates cardiocyte ultrastructure injury and apoptosis by blocking mitochondrial permeability transition in rats. Acta Cardiol. 2008 63(3):377-387.
[69] Baxter GF, Burley DS. Reperfusion and calculated RISKs: pharmacological postconditioning of human myocardium. Br J Pharmacol. 2008 153(1):1-3.
[70] Zatta AJ, Kin H, Yoshishige D, Jiang R, Wang N, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Caffrey JL, Vinten-Johansen J. Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation. Am J Physiol Heart Circ Physiol. 2008 294(3):H1444-1451.
[71] Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J Surg Res. 2008 145(2):287-294.
[72] Ji Y, Pang QF, Xu G, Wang L, Wang JK, Zeng YM. Exogenous hydrogen sulfide postconditioning protects isolated rat hearts against ischemia-reperfusion injury. Eur J Pharmacol. 2008 587(1-3):1-7.
[73] Murozono Y, Takahashi N, Shinohara T, Ooie T, Teshima Y, Hara M, Saikawa T, Yoshimatsu H. Hyperthermia-Induced Cardioprotection Is Potentiated by Ischemic Postconditioning in Rats. Exp Biol Med (Maywood). 2009.
[74] Luo W, Li B, Chen R, Huang R, Lin G. Effect of ischemic postconditioning in adult valve replacement. Eur J Cardiothorac Surg. 2008 33(2):203-208.
[75] Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary intervention for acute myocardial infarction: a benefit of postconditioning. Catheter Cardiovasc Interv. 2008 72(2):212-220.
[76] Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M. Postconditioning the human heart. Circulation. 2005 112(14):2143-2148.
[77] Ma X, Zhang X, Li C, Luo M. Effect of postconditioning on coronary blood flow velocity and endothelial function and LV recovery after myocardial infarction. J Interv Cardiol. 2006 19(5):367-375.
[78] Darling CE, Jiang R, Maynard M, Whittaker P, Vinten-Johansen J, Przyklenk K. Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2. Am J Physiol Heart Circ Physiol. 2005 289(4):H1618-1626.
[79] Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM. Postconditioning: a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res. 2004 95(3):230-232.
[80] Galagudza M, Kurapeev D, Minasian S, Valen G, Vaage J. Ischemic postconditioning: brief ischemia during reperfusion converts persistent ventricular fibrillation into regular rhythm. Eur J Cardiothorac Surg. 2004 25(6):1006-1010.
[81] Halkos ME, Kerendi F, Corvera JS, Wang NP, Kin H, Payne CS, Sun HY, Guyton RA, Vinten-Johansen J, Zhao ZQ. Myocardial protection with postconditioning is not enhanced by ischemic preconditioning. Ann Thorac Surg. 2004 78(3):961-969 discussion 969.
[82] Dow J, Bhandari A, Kloner RA. Ischemic postconditioning's benefit on reperfusion ventricular arrhythmias is maintained in the senescent heart. J Cardiovasc Pharmacol Ther. 2008 13(2):141-148.
[83] Dragoni S, Di Stolfo G, Sicuro S, Lisi M, Parker JD, Forconi S, Gori T. Postconditioning fails to prevent radial artery endothelial dysfunction induced by ischemia and reperfusion: evidence from a human in vivo study. Can J Physiol Pharmacol. 2006 84(6):611-615.
[84] Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury. Cardiovasc Res. 2003 60(3):617-625.
[85] Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M. PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res. 2006 69(1):178-185.
[86] Lim SY, Davidson SM, Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovasc Res. 2007 75(3):530-535.
[87] Liu XH, Zhang ZY, Sun S, Wu XD. Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock. 2008 30(4):422-427.
[88] Rey FE, Li XC, Carretero OA, Garvin JL, Pagano PJ. Perivascular superoxide anion contributes to impairment of endothelium-dependent relaxation: role of gp91(phox). Circulation. 2002 106(19):2497-2502.
[89] Bolli R, Patel BS, Jeroudi MO, Lai EK, McCay PB. Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone. J Clin Invest. 1988 82(2):476-485.
[90] Sun HY, Wang NP, Kerendi F, Halkos M, Kin H, Guyton RA, Vinten-Johansen J, Zhao ZQ. Hypoxic postconditioning reduces cardiomyocyte loss by inhibiting ROS generation and intracellular Ca2+ overload. Am J Physiol Heart Circ Physiol. 2005 288(4):H1900-1908.
[91] Sun K, Liu ZS, Sun Q. Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning. World J Gastroenterol. 2004 10(13):1934-1938.
[92] Petrishchev NN, Vlasov TD, Galagudza MM, Kurapeev DI, Minasian SM. [Myocardial ischemic postconditioning: a brief ischemia causes conversion of resistent reperfusion-induced ventricular fibrillation into the normal rhythm]. Ross Fiziol Zh Im I M Sechenova. 2004 90(9):1138-1144.
[93]刘秀华,唐朝枢.缺血再灌注损伤的防治——从实验室到临床.中华心血管病杂志. 2006 34(8):677-679.
[94] Zhao Z, Zang Y. Alternative cardioprotective strategy during reperfusion:postconditioning vs preconditioning [J]. Chin Heart J 2006 18(1):1-7, 13.
[95] Philipp S, Yang XM, Cui L, Davis AM, Downey JM, Cohen MV. Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res. 2006 70(2):308-314.
[96]王珏,高琴,沈佳,叶挺梅,夏强.阿片受体介导缺血后处理的心肌保护作用及其受体后机制. .浙江大学学报(医学版) 2007 36(1):7.
[97] Ventura C, Spurgeon H, Lakatta EG, Guarnieri C, Capogrossi MC. Kappa and delta opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. Circ Res. 1992 70(1):66-81.
[98] Xiao RP, Pepe S, Spurgeon HA, Capogrossi MC, Lakatta EG. Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells. Am J Physiol. 1997 272(2 Pt 2):H797-805.
[99] Kin H, Zatta AJ, Jiang R. Activation of opioid receptors mediates the infarct postconditioning. J Mol Cell Cardiol. 2005 38(5):827.
[100] Gross ER, Gross GJ. Ligand triggers of classical preconditioning and postconditioning. Cardiovasc Res. 2006 70(2):212-221.
[101] Ping P, Zhang J, Cao X, Li RC, Kong D, Tang XL, Qiu Y, Manchikalapudi S, Auchampach JA, Black RG, Bolli R. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol. 1999 276(5 Pt 2):H1468-1481.
[102] Fantinelli JC, Mosca SM. Comparative effects of ischemic pre and postconditioning on ischemia-reperfusion injury in spontaneously hypertensive rats (SHR). Mol Cell Biochem. 2007 296(1-2):45-51.
[103] Zatta AJ, Kin H, Lee G, Wang N, Jiang R, Lust R, Reeves JG, Mykytenko J, Guyton RA, Zhao ZQ, Vinten-Johansen J. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling. Cardiovasc Res. 2006 70(2):315-324.
[104]孙胜,高钰琪,高文祥,范明.缺氧诱导因子1与PI3K/Akt/mTOR信号转导通路.生命科学. 2005 17(4):311-314.
[105] Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002 296(5573):1655-1657.
[106] Fujita M, Asanuma H, Hirata A, Wakeno M, Takahama H, Sasaki H, Kim J, Takashima S, Tsukamoto O, Minamino T, Shinozaki Y, Tomoike H, Hori M, Kitakaze M.Prolonged transient acidosis during early reperfusion contributes to the cardioprotective effects of postconditioning. Am J Physiol Heart Circ Physiol. 2007 292(4):H2004-2008.
[107] Schwartz LM, Lagranha CJ. Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs. Am J Physiol Heart Circ Physiol. 2006 290(3):H1011-1018.
[108] Burley DS, Ferdinandy P, Baxter GF. Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. Br J Pharmacol. 2007 152(6):855-869.
[109] Cohen MV, Downey JM. Cardioprotection: spotlight on PKG. Br J Pharmacol. 2007 152(6):833-834.
[110] Takuma K, Phuagphong P, Lee E, Mori K, Baba A, Matsuda T. Anti-apoptotic effect of cGMP in cultured astrocytes: inhibition by cGMP-dependent protein kinase of mitochondrial permeable transition pore. J Biol Chem. 2001 276(51):48093-48099.
[111]刘秀华,苏静怡.缺血预处理的研究现状.生理科学进展. 2001 32(1):83-87.
[112]祝筱梅,刘秀华,蔡莉蓉,徐菲菲. p38丝裂素活化蛋白激酶介导低氧预处理诱导的内质网应激相关的心肌细胞保护.生理学报. 2006 58(5):463-470.
[113] Hausenloy DJ, Yellon DM. Survival kinases in ischemic preconditioning and postconditioning. Cardiovasc Res. 2006 70(2):240-253.
[114] Sun HY, Wang NP, Halkos M, Kerendi F, Kin H, Guyton RA, Vinten-Johansen J, Zhao ZQ. Postconditioning attenuates cardiomyocyte apoptosis via inhibition of JNK and p38 mitogen-activated protein kinase signaling pathways. Apoptosis. 2006 11(9):1583-1593.
[115]祝筱梅,刘秀华,蔡莉蓉.缺氧后处理对缺氧/复氧心肌细胞的保护作用及其机理研究.中国微循环. 2007 11(4):223-230.
[116] Kaiser RA, Liang Q, Bueno O, Huang Y, Lackey T, Klevitsky R, Hewett TE, Molkentin JD. Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo. J Biol Chem. 2005 280(38):32602-32608.
[117] Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. Cardiovasc Res. 2004 61(3):372-385.
[118] Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J. 1995 307 ( Pt 1):93-98.
[119] Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning Cardiovasc Res. 2002 55(3):534-543.
[120] Gomez L, Chavanis N, Argaud L, Chalabreysse L, Gateau-Roesch O, Ninet J, Ovize M. Fas-independent mitochondrial damage triggers cardiomyocyte death afterischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2005 289(5):H2153-2158.
[121] Irie H, Gao J, Gaudette GR, Cohen IS, Mathias RT, Saltman AE, Krukenkamp IB. Both metabolic inhibition and mitochondrial K(ATP) channel opening are myoprotective and initiate a compensatory sarcolemmal outward membrane current. Circulation. 2003 108 Suppl 1:II341-347.
[122] Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliaro P. Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol. 2006 101(2):180-189.
[123] Koseki T, Inohara N, Chen S, Nunez G. ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci U S A. 1998 95(9):5156-5160.
[124] Li YZ, Liu XH, Zhu XM, Cai LR. ARC contributes to the inhibitory effect of preconditioning on cardiomyocyte apoptosis. Apoptosis. 2007 12(9):1589-1595.
[125] Wu ZK, Pehkonen E, Laurikka J, Kaukinen L, Honkonen EL, Kaukinen S, Laippala P, Tarkka MR. The protective effects of preconditioning decline in aged patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2001 122(5):972-978.
[126] Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol. 2006 47(11):2277-2282.
[127] Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F. Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2005 100(4):295-310.
[128]祝筱梅,刘秀华.缺血-再灌注损伤防治的新方法——缺血后处理的研究现状.生理科学进展. 2007 38(3):261-265.
[129] Iliodromitis EK, Zoga A, Vrettou A, Andreadou I, Paraskevaidis IA, Kaklamanis L, Kremastinos DT. The effectiveness of postconditioning and preconditioning on infarct size in hypercholesterolemic and normal anesthetized rabbits. Atherosclerosis. 2006 188(2):356-362.
[130] Mykytenko J, Kerendi F, Reeves JG, Kin H, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao ZQ. Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol. 2007 102(1):90-100.
[131] Downey JM, Cohen MV. We think we see a pattern emerging here. Circulation. 2005 111(2):120-121.
[132] Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol.2005 288(2):H971-976.
[133] Laskey WK. Brief repetitive balloon occlusions enhance reperfusion during percutaneous coronary intervention for acute myocardial infarction: a pilot study. Catheter Cardiovasc Interv. 2005 65(3):361-367.
[134] Guo Y, Wu WJ, Qiu Y, Tang XL, Yang Z, Bolli R. Demonstration of an early and a late phase of ischemic preconditioning in mice. Am J Physiol. 1998 275(4 Pt 2):H1375-1387.
[135] Wang G, Liem DA, Vondriska TM, Honda HM, Korge P, Pantaleon DM, Qiao X, Wang Y, Weiss JN, Ping P. Nitric oxide donors protect murine myocardium against infarction via modulation of mitochondrial permeability transition. Am J Physiol Heart Circ Physiol. 2005 288(3):H1290-1295.
[136] Klein HH PS, Schaper J, Schaper W. The mechanism of the tetrazolium reaction in identifying experimental myocardial infarction. Virchows Arch. 1981(393):287-297.
[137] Schwarz ER, Somoano Y, Hale SL, Kloner RA. What is the required reperfusion period for assessment of myocardial infarct size using triphenyltetrazolium chloride staining in the rat J Thromb Thrombolysis. 2000 10(2):181-187.
[138] Goto M, Tsuchida A, Liu Y, Cohen MV, Downey JM. Transient inhibition of glucose uptake mimics ischemic preconditioning by salvaging ischemic myocardium in the rabbit heart. J Mol Cell Cardiol. 1995 27(9):1883-1894.
[139] Sack S, Mohri M, Arras M, Schwarz ER, Schaper W. Ischaemic preconditioning--time course of renewal in the pig. Cardiovasc Res. 1993 27(4):551-555.
[140] Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol. 1995 268(5 Pt 2):H2157-2161.
[141] Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996 94(9):2193-2200.
[142] Michael LH, Entman ML, Hartley CJ, Youker KA, Zhu J, Hall SR, Hawkins HK, Berens K, Ballantyne CM. Myocardial ischemia and reperfusion: a murine model. Am J Physiol. 1995 269(6 Pt 2):H2147-2154.
[143] Birnbaum Y, Hale SL, Kloner RA. Differences in reperfusion length following 30 minutes of ischemia in the rabbit influence infarct size, as measured by triphenyltetrazolium chloride staining. J Mol Cell Cardiol. 1997 29(2):657-666.
[144] Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003 92(8):873-880.
[145] Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res. 2008 102(1):131-135.
[146] Iliodromitis EK, Georgiadis M, Cohen MV, Downey JM, Bofilis E, Kremastinos DT. Protection from post-conditioning depends on the number of short ischemic insults inanesthetized pigs. Basic Res Cardiol. 2006 101(6):502-507.
[147] Liu P, Xu B, Cavalieri TA, Hock CE. Age-related difference in myocardial function and inflammation in a rat model of myocardial ischemia-reperfusion. Cardiovasc Res. 2002 56(3):443-453.
[148] Oudot A, Martin C, Busseuil D, Vergely C, Demaison L, Rochette L. NADPH oxidases are in part responsible for increased cardiovascular superoxide production during aging. Free Radic Biol Med. 2006 40(12):2214-2222.
[149] Fenton RA, Dickson EW, Dobson JG, Jr. Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart. Life Sci. 2005 77(26):3375-3388.
[150] Shinmura K, Tamaki K, Bolli R. Short-term caloric restriction improves ischemic tolerance independent of opening of ATP-sensitive K+ channels in both young and aged hearts. J Mol Cell Cardiol. 2005 39(2):285-296.
[151] Crews DE. Artificial environments and an aging population: designing for age-related functional losses. J Physiol Anthropol Appl Human Sci. 2005 24(1):103-109.
[152] Pahor M, Di Gennaro M, Cocchi A, Bernabei R, Carosella L, Carbonin P. Age-related incidence of reperfusion- and reoxygenation-induced ventricular tachyarrhythmias in the isolated rat heart. Gerontology. 1985 31(1):15-26.
[153] Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, Cacciatore F, Longobardi G, Rengo F. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol. 1996 27(7):1777-1786.
[154] Boucher F, Tanguy S, Besse S, Tresallet N, Favier A, de Leiris J. Age-dependent changes in myocardial susceptibility to zero flow ischemia and reperfusion in isolated perfused rat hearts: relation to antioxidant status. Mech Ageing Dev. 1998 103(3):301-316.
[155] Headrick JP. Aging impairs functional, metabolic and ionic recovery from ischemia-reperfusion and hypoxia-reoxygenation. J Mol Cell Cardiol. 1998 30(7):1415-1430.
[156] Cain BS, Meldrum DR, Joo KS, Wang JF, Meng X, Cleveland JC, Jr., Banerjee A, Harken AH. Human SERCA2a levels correlate inversely with age in senescent human myocardium. J Am Coll Cardiol. 1998 32(2):458-467.
[157] Lim CC, Liao R, Varma N, Apstein CS. Impaired lusitropy-frequency in the aging mouse: role of Ca(2+)-handling proteins and effects of isoproterenol. Am J Physiol. 1999 277(5 Pt 2):H2083-2090.
[158] Nitahara JA, Cheng W, Liu Y, Li B, Leri A, Li P, Mogul D, Gambert SR, Kajstura J, Anversa P. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats. J Mol Cell Cardiol. 1998 30(3):519-535.
[159] Abete P, Napoli C, Santoro G, Ferrara N, Tritto I, Chiariello M, Rengo F, Ambrosio G. Age-related decrease in cardiac tolerance to oxidative stress. J Mol Cell Cardiol.1999 31(1):227-236.
[160] Pepe S. Mitochondrial function in ischaemia and reperfusion of the ageing heart. Clin Exp Pharmacol Physiol. 2000 27(9):745-750.
[161] Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia--reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001 33(6):1065-1089.
[162] Higami Y, Shimokawa I. Apoptosis in the aging process. Cell Tissue Res. 2000 301(1):125-132.
[163] Phaneuf S, Leeuwenburgh C. Cytochrome c release from mitochondria in the aging heart: a possible mechanism for apoptosis with age. Am J Physiol Regul Integr Comp Physiol. 2002 282(2):R423-430.
[164] Ungvari Z, Csiszar A, Kaley G. Vascular inflammation in aging. Herz. 2004 29(8):733-740.
[165] Betsuyaku T, Kovacs A, Saffitz JE, Yamada KA. Cardiac structure and function in young and senescent mice heterozygous for a connexin43 null mutation. J Mol Cell Cardiol. 2002 34(2):175-184.
[166] Olsson MC, Palmer BM, Leinwand LA, Moore RL. Gender and aging in a transgenic mouse model of hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2001 280(3):H1136-1144.
[167] Heusch G, Buchert A, Feldhaus S, Schulz R. No loss of cardioprotection by postconditioning in connexin 43-deficient mice. Basic Res Cardiol. 2006 101(4):354-356.
[168] Dow J, Kloner RA. Postconditioning does not reduce myocardial infarct size in an in vivo regional ischemia rodent model. J Cardiovasc Pharmacol Ther. 2007 12(2):153-163.
[169] Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol. 2008 51(14):1393-1398.
[170] Fenton RA, Dickson EW, Meyer TE, Dobson JG, Jr. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol. 2000 32(7):1371-1375.
[171] Burns PG, Krunkenkamp IB, Calderone CA, Kirvaitis RJ, Gaudette GR, Levitsky S. Is the preconditioning response conserved in senescent myocardium Ann Thorac Surg. 1996 61(3):925-929.
[172] Krieg T, Qin Q, McIntosh EC, Cohen MV, Downey JM. ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases. Am J Physiol Heart Circ Physiol. 2002 283(6):H2322-2330.
[173] Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004 30(2):193-204.
[174] Martineau LC, Chadan SG, Parkhouse WS. Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse. Mech Ageing Dev. 1999 106(3):217-232.
[175] Centurione L, Antonucci A, Miscia S, Grilli A, Rapino M, Grifone G, Di Giacomo V, Di Giulio C, Falconi M, Cataldi A. Age-related death-survival balance in myocardium: an immunohistochemical and biochemical study. Mech Ageing Dev. 2002 123(4):341-350.
[176] Abete P, Testa G, Ferrara N, De Santis D, Capaccio P, Viati L, Calabrese C, Cacciatore F, Longobardi G, Condorelli M, Napoli C, Rengo F. Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats. Am J Physiol Heart Circ Physiol. 2002 282(6):H1978-1987.
[177] Steinbrecher KA, Wilson W, 3rd, Cogswell PC, Baldwin AS. Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription. Mol Cell Biol. 2005 25(19):8444-8455.
[178] Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res. 2002 90(4):377-379.
[179] Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH. Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell. 2001 105(6):721-732.
[180] Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004 113(11):1535-1549.
[181] van Weeren PC, de Bruyn KM, de Vries-Smits AM, van Lint J, Burgering BM. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB. J Biol Chem. 1998 273(21):13150-13156.
[182] Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999 401(6748):82-85.
[183] Matsui T, Tao J, del Monte F, Lee KH, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A. Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation. 2001 104(3):330-335.
[184] Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem. 1998 273(32):19929-19932.
[185] Murphy E, Steenbergen C. Inhibition of GSK-3beta as a target for cardioprotection: the importance of timing, location, duration and degree of inhibition. Expert Opin Ther Targets. 2005 9(3):447-456.
[186] Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res. 2000 87(4):309-315.
[187] Pagel PS, Krolikowski JG, Neff DA, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC. Inhibition of glycogen synthase kinase enhances isoflurane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth Analg. 2006 102(5):1348-1354.
[188] Davis RJ. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 268(20):14553-14556.
[189] Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004 61(3):448-460.
[190] Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC, Pagel PS. Role of Erk1/2, p70s6K, and eNOS in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anaesth. 2006 53(2):174-182.
[191] Peart JN, Gross GJ. Chronic exposure to morphine produces a marked cardioprotective phenotype in aged mouse hearts. Exp Gerontol. 2004 39(7):1021-1026.
[192] Bartling B, Friedrich I, Silber RE, Simm A. Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg. 2003 76(1):105-111.