缺氧缺血性脑损伤新生大鼠心肌细胞凋亡、影响因素及1，6-二磷酸果糖保护作用的研究
|
摘要
本实验建立H9c2大鼠心肌细胞缺氧缺血模型,采用MTT法测定细胞存活率、流式细胞术测定细胞凋亡率、免疫细胞化学法检测Cyt C及Caspase-3蛋白表达,并应用FDP进行干预。结果表明:缺氧12小时后H9c2细胞存活率降低、凋亡率升高,Cyt C及Caspase-3蛋白表达增高;FDP提高细胞存活率,降低细胞凋亡率及Cyt C、Caspase-3蛋白表达。结扎7日龄新生大鼠一侧颈总动脉后,吸入低浓度氧复制HIBD模型,证实了它是一个稳定、可重复性好,设备简单,可大规模应用的模拟新生儿HIBD的动物模型。在此模型基础上,实验分为3组:HIBD组、FDP组及NC组。应用TUNEL检测法发现HIBD后12h心肌细胞凋亡明显增高,72h达高峰,7d仍有少量凋亡存在;FDP组较HIBD组心肌细胞凋亡率降低。应用免疫组化法,首次研究线粒体通道上的凋亡相关基因Caspase-3、Bax、Bcl-2及Cyt C在新生大鼠HIBD后不同时间点心肌细胞的表达,结果表明:Caspase-3、Bax、Bcl-2及Cyt C蛋白表达增高,且与凋亡细胞数之间呈直线正相关;FDP抑制Bax、Caspase-3、Cyt C蛋白表达,提高Bcl-2蛋白表达及Bcl-2/Bax的比值。同时动态观察HIBD后血清MDA、SOD及NO含量,结果表明:HIBD后血清MDA、NO增高,SOD降低,MDA与凋亡细胞数之间呈直线正相关,SOD与凋亡细胞数呈直线负相关;FDP可降低MDA,增高SOD。提示FDP可能通过抑制心肌细胞凋亡而发挥保护心肌细胞的作用。
Neonatal hypoxic and ischemic encephalopathy (HIE) is a common disease in neonatal period and has high mortality and sequelae. Besides brain damage, it often causes functional disturbance of many organs. Heart is the most damaged organ. The usual reason of HIE is fetal distress in uterus and neonatal asphyxia. Asphyxia and hypoxia is pathogenesis of organ damage and functional disturbance. Until now, mechanism of heart injury about HIBD is unclear.
Recently apoptosis has become the major research focus all over the world. Now it has been confirmed that cardiomyocyte apoptosis resides in many physiological and pathological change of cardiovascular disease. At present the report about neurocyte apoptosis on HIE are seen repeatedly home and abroad., but there are few research about cardiomyocyte apoptosis,and expression on apoptosis related gene, free radicle, effect of nitrogen monoxidum for cardiomyocyte apoptosis have not reported yet. Cardiac muscle is a kind of tissue needing high oxygen. More and more evidences show chondriosome has basic effects in cell apoptosis. Therefore, it is necessary for us to study the factor about affecting cell apoptosis in chondriosome pervium. This study is about cardiomyocyte apoptosis at hypoxic- ischema, influencing factors and protective effect of fructose 1,6-diphosphote (FDP) for cardiomyocyte.
There are three parts in this study.
1. H9c2 rat cardiomyocyte in vitro culture lack oxygen 12 hours, then make HI models of cardiomyocyte in vitro. We observed survival rate of cardiomyocyte by MTT means, H9c2 cardiomyocyte apoptosis rate by Annexin-V/PI double fluorescent labeling flow cytometry (FCM), expression of Cyt C and Caspase-3 protein by Immunocytochemistry. We set up FDP high dose intervention group, low dose intervention group and normal control group, and then observe protective effect for H9c2 cardiomyocyte apoptosis.
2. At the base of vitro experiment ,this study prepared homoplastic HIBD animal models as human beings. We ligated one side common carotid artery of 7days rats, and reproduce HIBD model. For confirming its feasibility we use biochemistry rate to determine lactate dehydrogenase(LDH), isoenzyme of creatine kinase (CK) and blood gas analysis. At last common appearance, heart body, survival rate and weigh growth were observed.
3. To identify the presence of cardiomyocyte apoptosis, the time of apoptosis, apoptosis relation genes (Cyt C, Caspase-3, Bax and Bcl-2) and the effect of free radicle and nitric oxide (NO) on cardiomyocyte apoptosis, all rats in the study were divided into sham operation normal control group(NC group), HI model group, FDP interventing group(1g/kg, ip, immediately, 24h, 48h, 72h after hypoxia every time, together 4 times). At time of 1h、4h、12h、24h、48h、72h、7d after HIBD, rats were put to death by decapitation and heart tissues were obtained. Heart tissue pathological change were observed by HE dyeing, cardiomyocyte apoptosis were observed by deoxyuridine triphosphate-biotin nick end labeling (TUNEL), and Bax、Bcl-2、Cyt C、Caspase-3 protein gene expression relation to apoptosis by immunohistochemistry. Simultaneously we determined malondialdehyde (MDA), erythrocuprein (SOD), oxidize cytokine NO by TBA chromatometry, xanthine oxidase method, nitrate reductase method at different time points. We also approach effect of free radical and NO for cardiomyocyte apoptosis, and then we study the effect of apoptosis relation gene, free radicle and NO on cardiomyocyte apoptosis.
The results show:
1. MTT method determines survival rate of cardiomyocyte: the survival rate of HI groups was lower than that of the control group (P<0.05). The survival rate of FDP group was higher than that of HI group, and FDP high dose group, difference is significant statistically (P<0.05).
2. AnnexinV/PI (FCM) determines the change of apoptosis: Normal control group had little apoptosis, and apoptosis rates of HI groups were higher than that of normal control group. Apoptosis rates of FDP high dose group were lower than that of HI group, and difference is significant statistically (P<0.05). It showed that FDP may lead to resisting apoptosis.
3. HI group in light microscope by HE dying had cell shrinkage and nucleus became smaller.
4. Cyt C、Caspase-3 protein expression:There was weakly positive expression in cardiomyocyte kytoplasm of normal control group. Cyt C、Caspase-3 protein expression of HI group was obviously higher, but Cyt C、Caspase-3 protein expression of FDP group was lower than that of HI group, especially FDP high dose group (P<0.05). It showed that Cyt C、Caspase-3 can promote cardiomyocyte apoptosis and FDP can inhibit cardiomyocyte apoptosis by cutting down Cyt C、Caspase-3 protein expression.
5. After preparation of HIBD,Models rats showed up different HI symptoms, and with increasement of day age, ,the weight of HIBD group grow slowly and was lagged than normal control group. Rats in HIBD group had the following symptoms:heart rate fastly, weak heart muscle contraction, irregular rhythm, dull cardiac muscle and venous blood color. HIBD group PaO2, PaSO2, HCO3- and pH were lower than those of the control group, and showed hypoxemia and metabolic acidosis. The survival rate of control group was 95%, but HIBD group was 75%. Serum cardiac creatase CK and LDH of HIBD group were obviously higher than those of the control group. Based on the appearance, heart body, blood gas analysis and cardiac creatase determition confirmed that this model was simple, easy, repeatable, and feasible, consistant with myocardial anoxia and ischemic models.
6. HE dying: Cardiomyocyte of normal neonatal rats ranged regularly, edge sharpness, caryotheca and chromatospherite visible, but after HIBD cardiomyocyte ranged in disorder.
7. Apoptosis of all neonatal rats at different time after HI: There were positive cells in NC group by chance, but cardiomyocyte nucleus was blue. After 12 hours apoptosis cells began increasing, and nucleus of TUNEL positive apoptosis cells were brown. Then they increased gradually, and at 72 hours it reach the peak. At 7 days apoptosis cells reduced, but were still higher than normal control group. Apoptosis cells reduced gradully and it was clear at the time of 48-72 hours. This confirmed that FDP could inhibit cardiomyocyte apoptosis and the effect was obvious after using three or four times.
8. The results show that the expression of Cyt C in heart tissue is weakly positive in NC group. At the time of 12 hours, more positive cells appear in HIBD group. Cyt C was stained brown and appears to be trabs or particles in endochylema. Then the concentration of Cyt C multiplicated piecemeal, and the peak arrived at the time of 72 hours. Accompanied with the multiplition of Cyt C, apoptosis cells appear more. And it was suggested that the enhancement of Cyt C to apoptosis be possible in a further step. The expression of Caspase-3 in heart tissue of neonate rats was weakly positive in the normal contrast group. The color and distribution of Caspase-3 were the same as Cyt C. At the time of 12 hours, more positive cells appeared in HIBD group. Then the concentration of Caspase-3 multiplicated piecemeal, and it reached the peak at the time of 48 hours. The concentration appeared to be a slow descent. At the time of 7 days there was higher concentration than that of normal control group. With the multiplication of Caspase-3, the quantity of apoptosis cells became more. And it was also suggested that the enhancement of Caspase-3 to apoptosis be confirmed. The results of our experiment showed that the expression of Bcl-2 in heart tissue of neonate rats was weakly positive in the normal control groups. And it rised after HIBD. It reached the peak at the time of 48 hours and then descended. In contrast, the expression of Bax can be seen in the heart issue in NC group and the expression was noticeable after HIBD. The ratio of Bcl-2 and Bax reduced after HIBD. The result showed that Bax can activate the process of apoptosis and the effect of Bcl-2 was inverse. The process of cardiomyocyte apoptosis was depressed in different degree in FDP intervention group by the way of decreasing the expression of Cyt C and Caspase-3. The results of higher Bcl-2/Bax in FDP intervention group than that in HIBD group showed that the contribution of FDP had the business with Bcl-2 protein.
9. The multiplication of MDA after HIBD began at the time of 4 hours, and it reached the peak at the time of 48 hours, then lowered down and appeared normal after 7days by observing the change of MDA、SOD、NO at different time points. The results indicated that lipoid peroxidation existed after HIBD. LPO emerged after the reaction of free radical and unsaturated fatty acid. The main metabolic product of LPO would promote the enhancement of MDA. And the multiplication of MDA had the positive correlation with cell apoptosis numbers.The concentration of SOD decreased at the time of 4 hours, and reach the lowest level at the time of 48h, and then recovered slowly. The multiplication of SOD had the negative correlation with cell apoptosis. This showed that multiplication of MDA and concentration of SOD loss may promote apoptosis emergence. Level of NO began at the time of 4 hours, and the peak reached at the time of 24 hours, then remained at higher level and appeared normal after 7 days. It showed that level of NO did not have the positive correlation with cell apoptosis, but had negative correlation with SOD and the positive correlation with MDA.Therefore, NO maybe promote cardiomyocyte apoptosis by indirect free radicle damage. In this experiment it was observed the change of MDA、SOD、NO in FDP group and effect after therapy 48-72 hours by FDP was better than HIBD group. It confirmed that FDP can resist oxygen free radical antioxidation.
In summary, cardiomyocyte apoptosis after HIBD is very complicated, chondrosome may play an important role and the upper component element is oxidative stress mechanism of free radicle and NO. Expression of Bcl-2 gene on mitochondria membrane may be lower regulateing component element. Then by the mechanism of Cyt C release and Caspase-3 activation, cardiomyocyte apoptosis is induced.Regulation mechanism of cardiomyocyte apoptosis is very complicated, and it relates to many component element including influencing factors, signal passage and gene regulation.Many factors participate in every component element. This study observed the expression of Caspase-3, Bcl-2, Bax and Cyt C in plastiosome passage and MDA, SOD, NO. To some degree,there must be some limitations in explaining the mechanism of cardiomyocyte apoptosis of neonatal rats by HIBD. It should be studied deeply.
Neonatal hypoxic and ischemic encephalopathy (HIE) is a common disease in neonatal period and has high mortality and sequelae. Besides brain damage, it often causes functional disturbance of many organs. Heart is the most damaged organ. The usual reason of HIE is fetal distress in uterus and neonatal asphyxia. Asphyxia and hypoxia is pathogenesis of organ damage and functional disturbance. Until now, mechanism of heart injury about HIBD is unclear.
Recently apoptosis has become the major research focus all over the world. Now it has been confirmed that cardiomyocyte apoptosis resides in many physiological and pathological change of cardiovascular disease. At present the report about neurocyte apoptosis on HIE are seen repeatedly home and abroad., but there are few research about cardiomyocyte apoptosis,and expression on apoptosis related gene, free radicle, effect of nitrogen monoxidum for cardiomyocyte apoptosis have not reported yet. Cardiac muscle is a kind of tissue needing high oxygen. More and more evidences show chondriosome has basic effects in cell apoptosis. Therefore, it is necessary for us to study the factor about affecting cell apoptosis in chondriosome pervium. This study is about cardiomyocyte apoptosis at hypoxic- ischema, influencing factors and protective effect of fructose 1,6-diphosphote (FDP) for cardiomyocyte.
There are three parts in this study.
1. H9c2 rat cardiomyocyte in vitro culture lack oxygen 12 hours, then make HI models of cardiomyocyte in vitro. We observed survival rate of cardiomyocyte by MTT means, H9c2 cardiomyocyte apoptosis rate by Annexin-V/PI double fluorescent labeling flow cytometry (FCM), expression of Cyt C and Caspase-3 protein by Immunocytochemistry. We set up FDP high dose intervention group, low dose intervention group and normal control group, and then observe protective effect for H9c2 cardiomyocyte apoptosis.
2. At the base of vitro experiment ,this study prepared homoplastic HIBD animal models as human beings. We ligated one side common carotid artery of 7days rats, and reproduce HIBD model. For confirming its feasibility we use biochemistry rate to determine lactate dehydrogenase(LDH), isoenzyme of creatine kinase (CK) and blood gas analysis. At last common appearance, heart body, survival rate and weigh growth were observed.
3. To identify the presence of cardiomyocyte apoptosis, the time of apoptosis, apoptosis relation genes (Cyt C, Caspase-3, Bax and Bcl-2) and the effect of free radicle and nitric oxide (NO) on cardiomyocyte apoptosis, all rats in the study were divided into sham operation normal control group(NC group), HI model group, FDP interventing group(1g/kg, ip, immediately, 24h, 48h, 72h after hypoxia every time, together 4 times). At time of 1h、4h、12h、24h、48h、72h、7d after HIBD, rats were put to death by decapitation and heart tissues were obtained. Heart tissue pathological change were observed by HE dyeing, cardiomyocyte apoptosis were observed by deoxyuridine triphosphate-biotin nick end labeling (TUNEL), and Bax、Bcl-2、Cyt C、Caspase-3 protein gene expression relation to apoptosis by immunohistochemistry. Simultaneously we determined malondialdehyde (MDA), erythrocuprein (SOD), oxidize cytokine NO by TBA chromatometry, xanthine oxidase method, nitrate reductase method at different time points. We also approach effect of free radical and NO for cardiomyocyte apoptosis, and then we study the effect of apoptosis relation gene, free radicle and NO on cardiomyocyte apoptosis.
The results show:
1. MTT method determines survival rate of cardiomyocyte: the survival rate of HI groups was lower than that of the control group (P<0.05). The survival rate of FDP group was higher than that of HI group, and FDP high dose group, difference is significant statistically (P<0.05).
2. AnnexinV/PI (FCM) determines the change of apoptosis: Normal control group had little apoptosis, and apoptosis rates of HI groups were higher than that of normal control group. Apoptosis rates of FDP high dose group were lower than that of HI group, and difference is significant statistically (P<0.05). It showed that FDP may lead to resisting apoptosis.
3. HI group in light microscope by HE dying had cell shrinkage and nucleus became smaller.
4. Cyt C、Caspase-3 protein expression:There was weakly positive expression in cardiomyocyte kytoplasm of normal control group. Cyt C、Caspase-3 protein expression of HI group was obviously higher, but Cyt C、Caspase-3 protein expression of FDP group was lower than that of HI group, especially FDP high dose group (P<0.05). It showed that Cyt C、Caspase-3 can promote cardiomyocyte apoptosis and FDP can inhibit cardiomyocyte apoptosis by cutting down Cyt C、Caspase-3 protein expression.
5. After preparation of HIBD,Models rats showed up different HI symptoms, and with increasement of day age, ,the weight of HIBD group grow slowly and was lagged than normal control group. Rats in HIBD group had the following symptoms:heart rate fastly, weak heart muscle contraction, irregular rhythm, dull cardiac muscle and venous blood color. HIBD group PaO2, PaSO2, HCO3- and pH were lower than those of the control group, and showed hypoxemia and metabolic acidosis. The survival rate of control group was 95%, but HIBD group was 75%. Serum cardiac creatase CK and LDH of HIBD group were obviously higher than those of the control group. Based on the appearance, heart body, blood gas analysis and cardiac creatase determition confirmed that this model was simple, easy, repeatable, and feasible, consistant with myocardial anoxia and ischemic models.
6. HE dying: Cardiomyocyte of normal neonatal rats ranged regularly, edge sharpness, caryotheca and chromatospherite visible, but after HIBD cardiomyocyte ranged in disorder.
7. Apoptosis of all neonatal rats at different time after HI: There were positive cells in NC group by chance, but cardiomyocyte nucleus was blue. After 12 hours apoptosis cells began increasing, and nucleus of TUNEL positive apoptosis cells were brown. Then they increased gradually, and at 72 hours it reach the peak. At 7 days apoptosis cells reduced, but were still higher than normal control group. Apoptosis cells reduced gradully and it was clear at the time of 48-72 hours. This confirmed that FDP could inhibit cardiomyocyte apoptosis and the effect was obvious after using three or four times.
8. The results show that the expression of Cyt C in heart tissue is weakly positive in NC group. At the time of 12 hours, more positive cells appear in HIBD group. Cyt C was stained brown and appears to be trabs or particles in endochylema. Then the concentration of Cyt C multiplicated piecemeal, and the peak arrived at the time of 72 hours. Accompanied with the multiplition of Cyt C, apoptosis cells appear more. And it was suggested that the enhancement of Cyt C to apoptosis be possible in a further step. The expression of Caspase-3 in heart tissue of neonate rats was weakly positive in the normal contrast group. The color and distribution of Caspase-3 were the same as Cyt C. At the time of 12 hours, more positive cells appeared in HIBD group. Then the concentration of Caspase-3 multiplicated piecemeal, and it reached the peak at the time of 48 hours. The concentration appeared to be a slow descent. At the time of 7 days there was higher concentration than that of normal control group. With the multiplication of Caspase-3, the quantity of apoptosis cells became more. And it was also suggested that the enhancement of Caspase-3 to apoptosis be confirmed. The results of our experiment showed that the expression of Bcl-2 in heart tissue of neonate rats was weakly positive in the normal control groups. And it rised after HIBD. It reached the peak at the time of 48 hours and then descended. In contrast, the expression of Bax can be seen in the heart issue in NC group and the expression was noticeable after HIBD. The ratio of Bcl-2 and Bax reduced after HIBD. The result showed that Bax can activate the process of apoptosis and the effect of Bcl-2 was inverse. The process of cardiomyocyte apoptosis was depressed in different degree in FDP intervention group by the way of decreasing the expression of Cyt C and Caspase-3. The results of higher Bcl-2/Bax in FDP intervention group than that in HIBD group showed that the contribution of FDP had the business with Bcl-2 protein.
9. The multiplication of MDA after HIBD began at the time of 4 hours, and it reached the peak at the time of 48 hours, then lowered down and appeared normal after 7days by observing the change of MDA、SOD、NO at different time points. The results indicated that lipoid peroxidation existed after HIBD. LPO emerged after the reaction of free radical and unsaturated fatty acid. The main metabolic product of LPO would promote the enhancement of MDA. And the multiplication of MDA had the positive correlation with cell apoptosis numbers.The concentration of SOD decreased at the time of 4 hours, and reach the lowest level at the time of 48h, and then recovered slowly. The multiplication of SOD had the negative correlation with cell apoptosis. This showed that multiplication of MDA and concentration of SOD loss may promote apoptosis emergence. Level of NO began at the time of 4 hours, and the peak reached at the time of 24 hours, then remained at higher level and appeared normal after 7 days. It showed that level of NO did not have the positive correlation with cell apoptosis, but had negative correlation with SOD and the positive correlation with MDA.Therefore, NO maybe promote cardiomyocyte apoptosis by indirect free radicle damage. In this experiment it was observed the change of MDA、SOD、NO in FDP group and effect after therapy 48-72 hours by FDP was better than HIBD group. It confirmed that FDP can resist oxygen free radical antioxidation.
In summary, cardiomyocyte apoptosis after HIBD is very complicated, chondrosome may play an important role and the upper component element is oxidative stress mechanism of free radicle and NO. Expression of Bcl-2 gene on mitochondria membrane may be lower regulateing component element. Then by the mechanism of Cyt C release and Caspase-3 activation, cardiomyocyte apoptosis is induced.Regulation mechanism of cardiomyocyte apoptosis is very complicated, and it relates to many component element including influencing factors, signal passage and gene regulation.Many factors participate in every component element. This study observed the expression of Caspase-3, Bcl-2, Bax and Cyt C in plastiosome passage and MDA, SOD, NO. To some degree,there must be some limitations in explaining the mechanism of cardiomyocyte apoptosis of neonatal rats by HIBD. It should be studied deeply.
引文
1. Chan PH. Role of oxidants in ischemic brain damage [J]. Stroke, 1996, 27(6):1124-1129.
2. Edwards AD, Yue X, Cox P, et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury [J]. Pediatr Res, 1997, 42(5):684-689.
3. 匡培根, 李振洲, 张凤英, 等. 东菱克栓酶对沙土鼠缺血性脑血管病引起的脑水肿的影响[J]. 中国新药杂志, 1995, 4(1): 56-59.
4. Thompson CB. Apoptosis in the pathogenesis and treatment of disease [J]. Science, 1995, 267(5203):1456-1462.
5. Matoba S, Tatsumi T, Keira N, et al. Cardioprotective effect of angiotensin-converting enzyme inhibition against hypoxia/reoxygenation injury in cultured rat cardiac myocytes[J]. Circulation, 1999, 99(6):817-822.
6. Meier P, Finch A, Evan G. Apoptosis in development [J]. Nature, 2000, 407(6805):796-801.
7. Kang PM, Haunstetter A, Aoki H, et al. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation [J]. Circ Res, 2000, 87 (2):118-125.
8. Hasenfuss G. Animal models of human cardiovascular disease, heart failure and hypertrophy [J]. Cardiovasc Res, 1998, 39(1):60-76.
9. 李刚, 马沛然, 杨波, 等. 新生大鼠脑缺氧缺血模型心肌细胞凋亡的研究[J]. 实用儿科临床杂志, 2003, 18(3):174-176.
10. Mattson MP, Kroemer G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection [J]. Trends Mol Med, 2003, 9(5):196-205.
11. Kiefer MC, Brauer MJ, Powers VC, et al. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak [J]. Nature, 1995, 374(6524): 736-739.
12. Takayama S, Sato T, Krajewski S, et al. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity [J]. Cell, 1995, 80(2):279-284.
13. Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy [J]. Biochim Biophys Acta, 1998, 1366(1-2):177-196.
14. Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing [J]. J Biol Chem, 2000, 275(33):25130-25138.
15. Chandel NS, Maltepe E, Goldwasser E, et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription [J]. Proc Natl Acad Sci U S A, 1998, 95(20):11715-11720.
16. Weiland U, Haendeler J, Ihling C, et al. Inhibition of endogenous nitric oxide synthase potentiates ischemia-reperfusion-induced myocardial apoptosis via a caspase-3 dependent pathway [J]. Cardiovasc Res, 2000, 45(3):671-678.
17. Stefanelli C, Pignatti C, Tantini B, et al. Nitric oxide can function as either a killer molecule or an antiapoptotic effector in cardiomyocytes [J]. Biochim Biophys Acta, 1999, 1450(3):406-413.
18. Pinsky DJ, Aji W, Szabolcs M, et al. Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture [J]. Am J Physiol, 1999, 277(3 Pt 2):H1189-1199.
19. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. Br J Cancer, 1972, 26(4):239-257.
20. Johnson EM Jr, Greenlund LJ, Akins PT, et al. Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury [J]. J Neurotrauma, 1995, 12(5):843-852.
21. Gottlieb RA, Burleson KO, Kloner RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes [J]. J Clin Invest, 1994, 94(4):1621-1628.
22. Fisher SA, Langille BL, Srivastava D. Apoptosis during cardiovascular development [J]. Circ Res, 2000, 87(10):856-864.
23. Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease [J]. Am J Pathol, 1990, 136(3):593-608.
24. Negoescu A, Lorimier P, Labat-Moleur F, et al. In situ apoptotic cell labeling by the TUNEL method: improvement and evaluation on cell preparations [J]. J Histochem Cytochem, 1996, 44(9):959-968.
25. Misao J, Hayakawa Y, Ohno M, et al. Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction [J]. Circulation, 1996, 94(7):1506-1512.
26. Tsujimoto Y, Cossman J, Jaffe E, et al. Involvement of the bcl-2 gene in human follicular lymphoma [J]. Science, 1985, 228(4706):1440-1443.
27. O’Neill J, Manion M, Schwartz P, et al. Promises and challenges oftargeting Bcl-2 anti-apoptotic proteins for cancer therapy [J]. Biochim Biophys Acta, 2004, 1705(1):43-51.
28. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival [J]. Science, 1998, 281(5381):1322-1326.
29. De Jong D, Prins FA, Mason DY, et al. Sub cellular localization of the bcl-2 protein in malignant and normal lymphoid cells [J]. Cancer Res, 1994, 54(1):256-260.
30. Jacobson MD, Burne JF, King MP, et al. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA [J]. Nature, 1993, 361(6410):365-369.
31. Zimowska W, Motyl T, Skierski J, et al. Apoptosis and Bcl-2 protein changes in L1210 leukaemic cells exposed to oxidative stress [J]. Apoptosis, 1997; 2(6):529-539.
32. Baffy G, Miyashita T, Williamson JR, et al. Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production [J]. J Biol Chem, 1993, 268(9):6511-6519.
33. Reed JC. Bcl-2 and the regulation of programmed cell death [J]. J Cell Biol, 1994, 124(1-2):1-6.
34. Hockenbery DM, Oltvai ZN, Yin XM, et al. Bcl-2 functions in an antioxidant pathway to prevent apoptosis [J]. Cell, 1993, 75(2):241-251.
35. Gottlieb RA,Engler RL, Apoptosis in myocardial ischemia reperfusion. Ann N Y Acad Sci, 1999, 874:412-426.
36. Hochhauser E, Kivity S, Offen D, et al. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice [J]. Am J PhysiolHeart Circ Physiol, 2003, 284(6):H2351-2359.
37. Reed JC. CytochromeC: can't live with it-can't live without it [J]. Cell, 1997,91(5) :527-537.
38. Kato GJ, Dang CV. Function of the c-Myc oncoprotein [J]. FASEB J, 1992, 6(12):3065-3072.
39. Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein [J]. Cell. 1992, 69(1):119-128.
40. Shi Y, Glynn JM, Guilbert LJ, et al. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas [J]. Science, 1992, 257(5067):212-214.
41. Abbas AK. Die and let live: eliminating dangerous lymphocytes [J]. Cell, 1996, 84(5):655-657.
42. Griffith TS, Ferguson TA. The role of FasL-induced apoptosis in immune privilege [J]. Immunol Today, 1997, 18(5):240-244.
43. Orlinick JR, Vaishnaw AK, Elkon KB. Structure and function of Fas/Fas ligand [J]. Int Rev Immunol, 1999; 18(4):293-308.
44. Sakata K, Sakata A, Kong L, et al. Role of Fas/FasL interaction in physiology and pathology: the good and the bad [J]. Clin Immunol Immunopathol, 1998, 87(1):1-7.
45. Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure [J]. Am J Pathol, 1996, 148(1):141-149.
46. Liu Y, Cigola E, Cheng W, et al. Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs [J]. Lab Invest. 1995 Dec;73(6):771-787.
47. Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death [J]. J Clin Invest, 1995, 96(5):2247-2259.
48. Schumann H, Morawietz H, Hakim K, et al. Alternative splicing of the primary Fas transcript generating soluble Fas antagonists is suppressed in the failing human ventricular myocardium [J]. Biochem Biophys Res Commun, 1997, 239(3):794-798.
49. Hulla JE, Schneider RP. Structure of the rat p53 tumor suppressor gene [J]. Nucleic Acids Res, 1993, 21(3):713-717.
50. Lee JM, Bernstein A. p53 mutations increase resistance to ionizing radiation [J]. Proc Natl Acad Sci U S A, 1993, 90(12):5742-5746.
51. Long X, Boluyt MO, Hipolito ML, et al. p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes [J]. J Clin Invest, 1997, 99(11):2635-2643.
52. Bialik S, Geenen DL, Sasson IE, et al. Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53 [J]. J Clin Invest, 1997, 100(6):1363-1372.
53. Budihardjo I, Oliver H, Lutter M, et al. Biochemical pathways of caspase activation during apoptosis [J]. Annu Rev Cell Dev Biol, 1999, 15:269-290.
54. Saikumar P, Dong Z, Mikhailov V, et al. Apoptosis: definition, mechanisms, and relevance to disease [J]. Am J Med, 1999, 107(5):489-506.
55. Eastman A, Rigas JR. Modulation of apoptosis signaling pathways and cell cycle regulation [J]. Semin Oncol, 1999, 26(5 Suppl 16):7-16; discussion 41-42.
56. 李玲. 细胞凋亡的分子机制及其调控因子. 国外医学·免疫学分册, 2002, 25 (6): 317-320.
57. 马大龙. 新细胞因子及细胞凋亡基因的发现与功能研究. 北京大学学报:医学版, 2002, 34 (5): 488-492.
58. 程永波. 细胞凋亡相关基因研究现状. 现代医药卫生, 2003, 19 (10): 1270-1272.
59. Hirsch T, Susin SA, Marzo I, et al. Mitochondrial permeability transition in apoptosis and necrosis [J]. Cell Biol Toxicol, 1998, 14(2):141-145.
60. Zhou P, Chou J, Olea RS, et al. Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: a structural basis for specific adaptor/caspase interaction [J]. Proc Natl Acad Sci U S A, 1999, 96(20):11265-11270.
61. Raha S, Robinson BH. Mitochondria, oxygen free radicals, and apoptosis. Am J Med Genet, 2001, 106(1):62-70.
62. Uechi Y, Yoshioka H, Morikawa D, et al. Stability of membrane potential in heart mitochondria: single mitochondrion imaging [J]. Biochem Biophys Res Commun, 2006, 344(4):1094-1101.
63. Sharov VG, Sabbah HN, Ali AS, et al. Abnormalities of cardiocytes in regions bordering fibrous scars of dogs with heart failure [J]. Int J Cardiol, 1997, 60(3):273-279.
64. Chen E, Proestou G, Bourbeau D, et al. Rapid up-regulation of peptide elongation factor EF-1alpha protein levels is an immediate early event during oxidative stress-induced apoptosis [J]. Exp Cell Res, 2000, 259(1):140-148.
65. Cook SA, Sugden PH, Clerk A. Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential [J]. Circ Res,1999, 85(10):940-949.
66. Nakamura K, Bossy-Wetzel E, Burns K, et al. Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis [J]. J Cell Biol, 2000, 150(4):731-740.
67. Hammou Oubrahim, Jun Wang, Earl R, et al. Molecular cloning and characterization of murine caspase-12 gene promoter. Proc Natl Acad Sci USA, 2005, 102 (7): 2322–2327.
68. Bartling B, Milting H, Schumann H, et al. Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure [J]. Circulation, 1999 Nov 9; 100(19 Suppl): II216-223.
69. Feuerstein GZ. Apoptosis in cardiac diseases—new opportunities for novel therapeutics for heart diseases [J]. Cardiovasc Drugs Ther, 1999, 13(4): 289-294.
70. 张宏, 苏怡凡, 李娟. NO、NOS 及 MDA 与伴心肌损伤的新生儿缺氧缺血脑病关系探讨[J]. 卫生职业教育, 2006, 24(19):112-113.
71. Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes [J]. Circ Res, 1994, 75(3):426-433.
72. Ladilov Y, Efe O, Schafer C, et al. Reoxygenation-induced rigor-type contracture [J]. J Mol Cell Cardiol, 2003, 35(12):1481-1490.
73. 侯金珍, 范睦蕾, 郭素琼, 等. 新生儿超氧化物歧化酶及其临床意义[J]. 北京医学, 1995, 17(2):75-77.
74. Zweier JL, Rayburn BK, Flaherty JT, et al. Recombinant superoxidedismutase reduces oxygen free radical concentrations in reperfused myocardium [J]. J Clin Invest, 1987, 80(6):1728-1734.
75. Kirshenbaum LA, Singal PK. Changes in antioxidant enzymes in isolated cardiac myocytes subjected to hypoxia-reoxygenation [J]. Lab Invest, 1992, 67(6):796-803.
76. Vanden Hoek TL, Becker LB, Shao Z, et al. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes [J]. J Biol Chem, 1998, 273(29):18092-18098.
77. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium [J]. Circ Res, 1996, 79(5):949-956.
78. Maulik N, Yoshida T, Das DK. Oxidative stress developed during the reperfusion of ischemic myocardium induces apoptosis [J]. Free Radic Biol Med, 1998, 24(5):869-875.
79. Brown GC. Nitric oxide and mitochondrial respiration [J]. Biochim Biophys Acta, 1999, 1411(2-3):351-369.
80. Shoskes DA, Xie Y, Gonzalez-Cadavid NF. Nitric oxide synthase activity in renal ischemia-reperfusion injury in the rat: implications for renaltransplantation[J]. Transplantation, 1997,63(4):495-500.
81. Shiva S, Brookes PS, Patel RP, et al. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase [J]. Proc Natl Acad Sci U S A, 2001, 98(13):7212-7217.
82. Poderoso JJ, Carreras MC, Lisdero C, et al. Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles [J]. Arch Biochem Biophys, 1996, 328(1):85-92.
83. Tatsumi T, Matoba S, Kawahara A, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes [J]. J Am Coll Cardiol, 2000, 35(5):1338-1346.
84. Zhao B, Shen J, Hu J, et al. Synergic effects of NO and oxygen free radicals in the injury of ischemia-reperfused myocardium—ESR studies on NO free radicals generated from ischemia-reperfused myocardium [J]. Sci China C Life Sci, 1996, 39(5):491-500.
85. Behar-Cohen FF, Heydolph S, Faure V, et al. Peroxynitrite cytotoxicity on bovine retinal pigmented epithelial cells in culture [J]. Biochem Biophys Res Commun, 1996, 226(3):842-849.
86. Shen JG, Quo XS, Jiang B, et al. Chinonin, a novel drug against cardiomyocyte apoptosis induced by hypoxia and reoxygenation [J]. Biochim Biophys Acta, 2000, 1500(2):217-226.
87. Ing DJ, Zang J, Dzau VJ, et al. Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x [J]. Circ Res, 1999, 84(1):21-33.
88. Nitahara JA, Cheng W, Liu Y, et al. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats [J]. J Mol Cell Cardiol, 1998, 30(3):519-535.
89. Markov AK, Oglethorpe NC, Blake TM, et al. Hemodynamic, electrocardiographic, and metabolic effects of fructose diphosphate on acute myocardial ischemia [J]. Am Heart J, 1980, 100(5):639-646.
90. Markov AK. Hemodynamics and metabolic effects of fructose 1-6 diphosphate in ischemia and shock—experimental and clinical observations[J]. Ann Emerg Med, 1986, 15(12):1470-1477.
91. Webb WR. Metabolic effects of fructose diphosphate in hypoxic and ischemic states [J]. J Thorac Cardiovasc Surg, 1984, 88(5 Pt 2):863-866.
92. Hardin CD, Roberts TM. Metabolism of exogenously applied fructose 1, 6-bisphosphate in hypoxic vascular smooth muscle [J]. Am J Physiol, 1994, 267(6 Pt 2): H2325-2332.
93. Lazzarino G, Hardin CD, Tavazzi B, et al. Myocardial metabolism of exogenous FDP is consistent with transport by a dicarboxylate transporter [J]. Am J Physiol Heart Circ Physiol, 2001, 281(6):H2654-2660.
94. Webb WR. Metabolic effects of fructose diphosphate in hypoxic and ischemic states [J]. J Thorac Cardiovasc Surg, 1984, 88(5 Pt 2):863-866.
95. 卢卫新, 戴瑞鸿. 1, 6-二磷酸果糖对组织缺血与缺氧的保护作用[J]. 中国临床医学, 2002, 9(1):91-92.
96. 张晶. 1,6-二磷酸果糖对缺血再灌注心肌的保护作用[J]. 中国循环杂志, 1991, 6(5):420.
97. Tavazzi B, Cerroni L, Di Pierro D, et al. Oxygen radical injury and loss of high-energy compounds in anoxic and reperfused rat heart: prevention by exogenous fructose-1,6-bisphosphate [J]. Free Radic Res Commun, 1990, 10(3):167-176.
98. Lazzarino G, Tavazzi B, Nuutinen M, et al. Protective effects of exogenously administered fructose-1,6-diphosphate from ischemia reperfusion damage induced on isolated rat heart [J]. Ital J Biochem, 1989, 38(4):251A-253A.
99. 赖平, 张洪泉, 马郁文, 等. 1, 6-二磷酸果糖对阿霉素心肌损伤防治作用的实验研究[J]. 山东医科大学学报, 1997, 35(3):242-244.
100. Cargnoni A, Condorelli E, Boraso A, et al. Role of timing of administration in the cardioprotective effect of fructose-1,6-bisphosphate [J]. Cardiovasc Drugs Ther, 1992, 6(3):209-217.
101. Hassinen IE, Nuutinen EM, Ito K,et al. Mechannism of the effect of Exogenous fructose 1, 6-bis-phosphateon myocardial energy metabolism [J]. Circulation, 1991,83(2) : 583-593.
102. Marchionni N, Conti A, De Alfieri W, et al. Hemodynamic and electrocardiographic effects of fructose-1,6-diphosphate in acute myocardial infarction [J]. Am J Cardiol, 1985, 56(4):266-269.
103. Daosukho C, Ittarat W, Lin SM, et al. Induction of manganese superoxide dismutase (MnSOD) mediates cardioprotective effect of tamoxifen (TAM) [J]. J Mol Cell Cardiol, 2005, 39(5):792-803.
104. Kaga S, Zhan L, Altaf E, et al. Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium [J]. J Mol Cell Cardiol, 2006, 40(1):138-147.
105. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium [J]. Circ Res, 1996, 79(5):949-956.
106. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors [J]. N Engl J Med, 1997, 336(9):633-640.
107. Liu JL, LeRoith D. Insulin-like growth factor I is essential for postnatal growth in response to growth hormone [J]. Endocrinology, 1999, 140(11):5178-5184.
108. Ren J, Walsh MF, Hamaty M, et al. Altered inotropic response to IGF-I indiabetic rat heart: influence of intracellular Ca2+ and NO [J]. Am J Physiol, 1998, 275(3 Pt 2):H823-830.
109. Buerke M, Murohara T, Skurk C, et al. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion [J]. Proc Natl Acad Sci U S A, 1995, 92(17):8031-8035.
110. Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy [J]. J Clin Invest, 1997, 100(8):1991-1999.
111. Jonassen AK, Sack MN, Mjos OD, et al. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling [J]. Circ Res, 2001 Dec 7; 89(12):1191-1198.
112. Gao F, Gao E, Yue TL, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation [J]. Circulation, 2002, 105(12):1497-1502.
113. Zhao ZQ, Morris CD, Budde JM, et al. Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion [J]. Cardiovasc Res, 2003, 59(1):132-142.
114. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger [J]. J Pharmacol Exp Ther, 1992, 263(1):92-98.
115. Yue TL, Ma XL, Wang X, et al. Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol [J].Circ Res, 1998, 82(2):166-174.
116. Packer M,Bristow MR,Cohn JN,et al.The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.New Eng1 J, Med. 1996, 334:1349-1397.
117. FeuersteinGZ, George P, Ruflolo RR, et al. Carvedilol updateⅢ: rational for use in congestive heart failure [J]. Drugs Today, 1995,31:307-326.
118. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro [J]. J Mol Cell Cardiol, 1997, 29(3): 859-870.
119. Goussev A, Sharov VG, Shimoyama H, et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure [J]. Am J Physiol, 1998, 275(2 Pt 2): H626-631.
120. 石熠慧, 汤雪明. 细胞凋亡信号的传递途径及其调控[J]. 细胞生物学杂志, 1999, 21(2):49-54.
121. Webster KA, Discher DJ, Bishopric NH. Cardioprotection in an in vitro model of hypoxic preconditioning [J]. J Mol Cell Cardiol, 1995, 27(1):453-458.
122. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. Br J Cancer, 1972, 26(4):239-257.
123. Yang BC, Zander DS, Mehta JL. Hypoxia-reoxygenation-induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta (1) [J]. J Pharmacol Exp Ther, 1999 Nov; 291(2):733-738.
124. 徐德民, 赵强, 陈安清, 等. 缺氧诱导离体心肌细胞凋亡的动物实验研究[J]. 中国临床医学, 2004, 11(5):714-716.
125. Vermes I, Haanen C, Steffens-Nakken H, et al. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V [J]. J Immunol Methods, 1995, 184(1):39-51.
126. Ekhterae D, Lin Z, Lundberg MS, et al. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells [J]. Circ Res, 1999, 85(12):e70-77.
127. Liu X, Kim CN, Yang J, et al. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c [J]. Cell, 1996, 86(1):147-157.
128. 张莉莉, 林久治, 蔡玲玲. 围产儿缺氧缺血性脑病 124 例的临床及病理学研究[J]. 中华妇产科杂志, 1996, 31(2):100-102.
129. 陈惠金, 周建德, 周泽汉, 等. 新生大鼠脑缺氧缺血损伤模型的制备[J]. 上海实验动物科学, 1999, 19(3):159-160.
130. Meade HM, Heading CE, Ball SJ. Glycylproline absorption in rats infected with Eimeria nieschulzi [J]. Biochem Soc Trans, 1981, 9(1):131-132.
131. Renolleau S, Aggoun-Zouaoui D, Ben-Ari Y, et al. A model of transient unilateral focal ischemia with reperfusion in the P7 neonatal rat: morphological changes indicative of apoptosis [J]. Stroke, 1998, 29(7):1454-1460.
132. 吴蓉洲, 李伟, 吴起朝, 等. 血清心肌肌钙蛋白-Ⅰ对新生儿窒息心肌损伤的诊断价值探讨[J]. 中国实用儿科杂志, 2000, 15(2):114.
133. 白希莲, 韩玉昆, 徐长新. 足月新生儿窒息后心功能的早期评价[J]. 中国实用儿科, 1994, 9(2):93-95.
134. 娜淇, 方幼萍, 王明中, 等. 乳酸脱氢酶同功酶测定对窒息新生儿缺氧损伤的评价[J]. 中国实用儿科杂志, 1994, 9(2):100-101.
135. 时锋, 许雯, 顾芳香. 新生儿窒息后心肌损害的评价[J]. 医学理论与实践, 2000, 13(9):560-561.
136. 池美珠, 陆中权. 新生儿窒息及脑损伤后心肌损害的研究[J]. 中国当代儿科杂志, 2000, 2(1):51-52.
137. Wijsman JH, Jonker RR, Keijzer R, et al. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA [J]. J Histochem Cytochem, 1993, 41(1):7-12.
138. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation [J]. J Cell Biol, 1992, 119(3):493-501.
139. Lim ML, Lum MG, Hansen TM, et al. On the release of cytochrome c from mitochondria during cell death signaling [J]. J Biomed Sci, 2002, 9(6 Pt 1): 488-506.
140. Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis [J]. J Cell Biol, 2003,160(1):65-75.
141. Kiechle FL, Zhang X. Apoptosis: biochemical aspects and clinical implications [J]. Clin Chim Acta, 2002, 326(1-2):27-45.
142. Higuchi M, Aggarwal BB, Yeh ET. Activation of CPP32-like protease in tumor necrosis factor-induced apoptosis is dependent on mitochondrial function [J]. J Clin Invest, 1997, 99(7):1751-1758.
143. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis [J]. Nat Med, 1997, 3(6):614-620.
144. Gross A, Jockel J, Wei MC, et al. Enforced dimerization of BAX results inits translocation, mitochondrial dysfunction and apoptosis [J]. EMBO J, 1998, 17(14):3878-3885.
145. Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked [J]. Science, 1997, 275(5303): 1129-1132.
146. Zhan Q, Fan S, Bae I, et al. Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene 1994;9(12): 3743-51.
147. Ballot DE, Rothberg AD, Davies VA, et al. Does hypoxemia prevent brain damage in birth asphyxia [J]? Med Hypotheses, 1993, 41(4):344-347.
148. Raha S, Robinson BH. Mitochondria, oxygen free radicals, and apoptosis [J]. Am J Med Genet, 2001, 106(1):62-70.
149. Turner NA, Xia F, Azhar G, et al. Oxidative stress induces DNA fragmentation and caspase activation via the c-Jun NH2-terminal kinase pathway in H9c2 cardiac muscle cells [J]. J Mol Cell Cardiol, 1998, 30(9): 1789-1801.
150. 李笑天, 潘明明, 庄依亮, 等. 胎儿缺氧和酸中毒对超氧化物歧化酶水平的影响[J]. 中华妇产科杂志, 2002, 37(4): 205-207.
151. 郑大同, 李述庭, 高雁翎, 等. 新生鼠缺氧缺血性脑损伤组织一氧化氮合酶基因表达及作用[J]. 中华儿科杂志, 2001, 39 (1):44.
152. Mery PF, Lohmann SM, Walter U, et al. Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes [J]. Proc Natl Acad Sci USA, 1991, 88(4):1197-201.
153. 黄忠耀, 朱洪生, 张有荣, 等. 卡托普利心脏停搏液对缺血再灌注心肌NOS 活性和 NO 产生的影响[J]. 中华胸心血管外科杂志, 1999, 15(3): 182-184.
2. Edwards AD, Yue X, Cox P, et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury [J]. Pediatr Res, 1997, 42(5):684-689.
3. 匡培根, 李振洲, 张凤英, 等. 东菱克栓酶对沙土鼠缺血性脑血管病引起的脑水肿的影响[J]. 中国新药杂志, 1995, 4(1): 56-59.
4. Thompson CB. Apoptosis in the pathogenesis and treatment of disease [J]. Science, 1995, 267(5203):1456-1462.
5. Matoba S, Tatsumi T, Keira N, et al. Cardioprotective effect of angiotensin-converting enzyme inhibition against hypoxia/reoxygenation injury in cultured rat cardiac myocytes[J]. Circulation, 1999, 99(6):817-822.
6. Meier P, Finch A, Evan G. Apoptosis in development [J]. Nature, 2000, 407(6805):796-801.
7. Kang PM, Haunstetter A, Aoki H, et al. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation [J]. Circ Res, 2000, 87 (2):118-125.
8. Hasenfuss G. Animal models of human cardiovascular disease, heart failure and hypertrophy [J]. Cardiovasc Res, 1998, 39(1):60-76.
9. 李刚, 马沛然, 杨波, 等. 新生大鼠脑缺氧缺血模型心肌细胞凋亡的研究[J]. 实用儿科临床杂志, 2003, 18(3):174-176.
10. Mattson MP, Kroemer G. Mitochondria in cell death: novel targets for neuroprotection and cardioprotection [J]. Trends Mol Med, 2003, 9(5):196-205.
11. Kiefer MC, Brauer MJ, Powers VC, et al. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak [J]. Nature, 1995, 374(6524): 736-739.
12. Takayama S, Sato T, Krajewski S, et al. Cloning and functional analysis of BAG-1: a novel Bcl-2-binding protein with anti-cell death activity [J]. Cell, 1995, 80(2):279-284.
13. Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy [J]. Biochim Biophys Acta, 1998, 1366(1-2):177-196.
14. Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing [J]. J Biol Chem, 2000, 275(33):25130-25138.
15. Chandel NS, Maltepe E, Goldwasser E, et al. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription [J]. Proc Natl Acad Sci U S A, 1998, 95(20):11715-11720.
16. Weiland U, Haendeler J, Ihling C, et al. Inhibition of endogenous nitric oxide synthase potentiates ischemia-reperfusion-induced myocardial apoptosis via a caspase-3 dependent pathway [J]. Cardiovasc Res, 2000, 45(3):671-678.
17. Stefanelli C, Pignatti C, Tantini B, et al. Nitric oxide can function as either a killer molecule or an antiapoptotic effector in cardiomyocytes [J]. Biochim Biophys Acta, 1999, 1450(3):406-413.
18. Pinsky DJ, Aji W, Szabolcs M, et al. Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture [J]. Am J Physiol, 1999, 277(3 Pt 2):H1189-1199.
19. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. Br J Cancer, 1972, 26(4):239-257.
20. Johnson EM Jr, Greenlund LJ, Akins PT, et al. Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury [J]. J Neurotrauma, 1995, 12(5):843-852.
21. Gottlieb RA, Burleson KO, Kloner RA, et al. Reperfusion injury induces apoptosis in rabbit cardiomyocytes [J]. J Clin Invest, 1994, 94(4):1621-1628.
22. Fisher SA, Langille BL, Srivastava D. Apoptosis during cardiovascular development [J]. Circ Res, 2000, 87(10):856-864.
23. Arends MJ, Morris RG, Wyllie AH. Apoptosis. The role of the endonuclease [J]. Am J Pathol, 1990, 136(3):593-608.
24. Negoescu A, Lorimier P, Labat-Moleur F, et al. In situ apoptotic cell labeling by the TUNEL method: improvement and evaluation on cell preparations [J]. J Histochem Cytochem, 1996, 44(9):959-968.
25. Misao J, Hayakawa Y, Ohno M, et al. Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction [J]. Circulation, 1996, 94(7):1506-1512.
26. Tsujimoto Y, Cossman J, Jaffe E, et al. Involvement of the bcl-2 gene in human follicular lymphoma [J]. Science, 1985, 228(4706):1440-1443.
27. O’Neill J, Manion M, Schwartz P, et al. Promises and challenges oftargeting Bcl-2 anti-apoptotic proteins for cancer therapy [J]. Biochim Biophys Acta, 2004, 1705(1):43-51.
28. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival [J]. Science, 1998, 281(5381):1322-1326.
29. De Jong D, Prins FA, Mason DY, et al. Sub cellular localization of the bcl-2 protein in malignant and normal lymphoid cells [J]. Cancer Res, 1994, 54(1):256-260.
30. Jacobson MD, Burne JF, King MP, et al. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA [J]. Nature, 1993, 361(6410):365-369.
31. Zimowska W, Motyl T, Skierski J, et al. Apoptosis and Bcl-2 protein changes in L1210 leukaemic cells exposed to oxidative stress [J]. Apoptosis, 1997; 2(6):529-539.
32. Baffy G, Miyashita T, Williamson JR, et al. Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production [J]. J Biol Chem, 1993, 268(9):6511-6519.
33. Reed JC. Bcl-2 and the regulation of programmed cell death [J]. J Cell Biol, 1994, 124(1-2):1-6.
34. Hockenbery DM, Oltvai ZN, Yin XM, et al. Bcl-2 functions in an antioxidant pathway to prevent apoptosis [J]. Cell, 1993, 75(2):241-251.
35. Gottlieb RA,Engler RL, Apoptosis in myocardial ischemia reperfusion. Ann N Y Acad Sci, 1999, 874:412-426.
36. Hochhauser E, Kivity S, Offen D, et al. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice [J]. Am J PhysiolHeart Circ Physiol, 2003, 284(6):H2351-2359.
37. Reed JC. CytochromeC: can't live with it-can't live without it [J]. Cell, 1997,91(5) :527-537.
38. Kato GJ, Dang CV. Function of the c-Myc oncoprotein [J]. FASEB J, 1992, 6(12):3065-3072.
39. Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein [J]. Cell. 1992, 69(1):119-128.
40. Shi Y, Glynn JM, Guilbert LJ, et al. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas [J]. Science, 1992, 257(5067):212-214.
41. Abbas AK. Die and let live: eliminating dangerous lymphocytes [J]. Cell, 1996, 84(5):655-657.
42. Griffith TS, Ferguson TA. The role of FasL-induced apoptosis in immune privilege [J]. Immunol Today, 1997, 18(5):240-244.
43. Orlinick JR, Vaishnaw AK, Elkon KB. Structure and function of Fas/Fas ligand [J]. Int Rev Immunol, 1999; 18(4):293-308.
44. Sakata K, Sakata A, Kong L, et al. Role of Fas/FasL interaction in physiology and pathology: the good and the bad [J]. Clin Immunol Immunopathol, 1998, 87(1):1-7.
45. Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure [J]. Am J Pathol, 1996, 148(1):141-149.
46. Liu Y, Cigola E, Cheng W, et al. Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs [J]. Lab Invest. 1995 Dec;73(6):771-787.
47. Cheng W, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death [J]. J Clin Invest, 1995, 96(5):2247-2259.
48. Schumann H, Morawietz H, Hakim K, et al. Alternative splicing of the primary Fas transcript generating soluble Fas antagonists is suppressed in the failing human ventricular myocardium [J]. Biochem Biophys Res Commun, 1997, 239(3):794-798.
49. Hulla JE, Schneider RP. Structure of the rat p53 tumor suppressor gene [J]. Nucleic Acids Res, 1993, 21(3):713-717.
50. Lee JM, Bernstein A. p53 mutations increase resistance to ionizing radiation [J]. Proc Natl Acad Sci U S A, 1993, 90(12):5742-5746.
51. Long X, Boluyt MO, Hipolito ML, et al. p53 and the hypoxia-induced apoptosis of cultured neonatal rat cardiac myocytes [J]. J Clin Invest, 1997, 99(11):2635-2643.
52. Bialik S, Geenen DL, Sasson IE, et al. Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53 [J]. J Clin Invest, 1997, 100(6):1363-1372.
53. Budihardjo I, Oliver H, Lutter M, et al. Biochemical pathways of caspase activation during apoptosis [J]. Annu Rev Cell Dev Biol, 1999, 15:269-290.
54. Saikumar P, Dong Z, Mikhailov V, et al. Apoptosis: definition, mechanisms, and relevance to disease [J]. Am J Med, 1999, 107(5):489-506.
55. Eastman A, Rigas JR. Modulation of apoptosis signaling pathways and cell cycle regulation [J]. Semin Oncol, 1999, 26(5 Suppl 16):7-16; discussion 41-42.
56. 李玲. 细胞凋亡的分子机制及其调控因子. 国外医学·免疫学分册, 2002, 25 (6): 317-320.
57. 马大龙. 新细胞因子及细胞凋亡基因的发现与功能研究. 北京大学学报:医学版, 2002, 34 (5): 488-492.
58. 程永波. 细胞凋亡相关基因研究现状. 现代医药卫生, 2003, 19 (10): 1270-1272.
59. Hirsch T, Susin SA, Marzo I, et al. Mitochondrial permeability transition in apoptosis and necrosis [J]. Cell Biol Toxicol, 1998, 14(2):141-145.
60. Zhou P, Chou J, Olea RS, et al. Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: a structural basis for specific adaptor/caspase interaction [J]. Proc Natl Acad Sci U S A, 1999, 96(20):11265-11270.
61. Raha S, Robinson BH. Mitochondria, oxygen free radicals, and apoptosis. Am J Med Genet, 2001, 106(1):62-70.
62. Uechi Y, Yoshioka H, Morikawa D, et al. Stability of membrane potential in heart mitochondria: single mitochondrion imaging [J]. Biochem Biophys Res Commun, 2006, 344(4):1094-1101.
63. Sharov VG, Sabbah HN, Ali AS, et al. Abnormalities of cardiocytes in regions bordering fibrous scars of dogs with heart failure [J]. Int J Cardiol, 1997, 60(3):273-279.
64. Chen E, Proestou G, Bourbeau D, et al. Rapid up-regulation of peptide elongation factor EF-1alpha protein levels is an immediate early event during oxidative stress-induced apoptosis [J]. Exp Cell Res, 2000, 259(1):140-148.
65. Cook SA, Sugden PH, Clerk A. Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential [J]. Circ Res,1999, 85(10):940-949.
66. Nakamura K, Bossy-Wetzel E, Burns K, et al. Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis [J]. J Cell Biol, 2000, 150(4):731-740.
67. Hammou Oubrahim, Jun Wang, Earl R, et al. Molecular cloning and characterization of murine caspase-12 gene promoter. Proc Natl Acad Sci USA, 2005, 102 (7): 2322–2327.
68. Bartling B, Milting H, Schumann H, et al. Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure [J]. Circulation, 1999 Nov 9; 100(19 Suppl): II216-223.
69. Feuerstein GZ. Apoptosis in cardiac diseases—new opportunities for novel therapeutics for heart diseases [J]. Cardiovasc Drugs Ther, 1999, 13(4): 289-294.
70. 张宏, 苏怡凡, 李娟. NO、NOS 及 MDA 与伴心肌损伤的新生儿缺氧缺血脑病关系探讨[J]. 卫生职业教育, 2006, 24(19):112-113.
71. Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes [J]. Circ Res, 1994, 75(3):426-433.
72. Ladilov Y, Efe O, Schafer C, et al. Reoxygenation-induced rigor-type contracture [J]. J Mol Cell Cardiol, 2003, 35(12):1481-1490.
73. 侯金珍, 范睦蕾, 郭素琼, 等. 新生儿超氧化物歧化酶及其临床意义[J]. 北京医学, 1995, 17(2):75-77.
74. Zweier JL, Rayburn BK, Flaherty JT, et al. Recombinant superoxidedismutase reduces oxygen free radical concentrations in reperfused myocardium [J]. J Clin Invest, 1987, 80(6):1728-1734.
75. Kirshenbaum LA, Singal PK. Changes in antioxidant enzymes in isolated cardiac myocytes subjected to hypoxia-reoxygenation [J]. Lab Invest, 1992, 67(6):796-803.
76. Vanden Hoek TL, Becker LB, Shao Z, et al. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes [J]. J Biol Chem, 1998, 273(29):18092-18098.
77. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium [J]. Circ Res, 1996, 79(5):949-956.
78. Maulik N, Yoshida T, Das DK. Oxidative stress developed during the reperfusion of ischemic myocardium induces apoptosis [J]. Free Radic Biol Med, 1998, 24(5):869-875.
79. Brown GC. Nitric oxide and mitochondrial respiration [J]. Biochim Biophys Acta, 1999, 1411(2-3):351-369.
80. Shoskes DA, Xie Y, Gonzalez-Cadavid NF. Nitric oxide synthase activity in renal ischemia-reperfusion injury in the rat: implications for renaltransplantation[J]. Transplantation, 1997,63(4):495-500.
81. Shiva S, Brookes PS, Patel RP, et al. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase [J]. Proc Natl Acad Sci U S A, 2001, 98(13):7212-7217.
82. Poderoso JJ, Carreras MC, Lisdero C, et al. Nitric oxide inhibits electron transfer and increases superoxide radical production in rat heart mitochondria and submitochondrial particles [J]. Arch Biochem Biophys, 1996, 328(1):85-92.
83. Tatsumi T, Matoba S, Kawahara A, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes [J]. J Am Coll Cardiol, 2000, 35(5):1338-1346.
84. Zhao B, Shen J, Hu J, et al. Synergic effects of NO and oxygen free radicals in the injury of ischemia-reperfused myocardium—ESR studies on NO free radicals generated from ischemia-reperfused myocardium [J]. Sci China C Life Sci, 1996, 39(5):491-500.
85. Behar-Cohen FF, Heydolph S, Faure V, et al. Peroxynitrite cytotoxicity on bovine retinal pigmented epithelial cells in culture [J]. Biochem Biophys Res Commun, 1996, 226(3):842-849.
86. Shen JG, Quo XS, Jiang B, et al. Chinonin, a novel drug against cardiomyocyte apoptosis induced by hypoxia and reoxygenation [J]. Biochim Biophys Acta, 2000, 1500(2):217-226.
87. Ing DJ, Zang J, Dzau VJ, et al. Modulation of cytokine-induced cardiac myocyte apoptosis by nitric oxide, Bak, and Bcl-x [J]. Circ Res, 1999, 84(1):21-33.
88. Nitahara JA, Cheng W, Liu Y, et al. Intracellular calcium, DNase activity and myocyte apoptosis in aging Fischer 344 rats [J]. J Mol Cell Cardiol, 1998, 30(3):519-535.
89. Markov AK, Oglethorpe NC, Blake TM, et al. Hemodynamic, electrocardiographic, and metabolic effects of fructose diphosphate on acute myocardial ischemia [J]. Am Heart J, 1980, 100(5):639-646.
90. Markov AK. Hemodynamics and metabolic effects of fructose 1-6 diphosphate in ischemia and shock—experimental and clinical observations[J]. Ann Emerg Med, 1986, 15(12):1470-1477.
91. Webb WR. Metabolic effects of fructose diphosphate in hypoxic and ischemic states [J]. J Thorac Cardiovasc Surg, 1984, 88(5 Pt 2):863-866.
92. Hardin CD, Roberts TM. Metabolism of exogenously applied fructose 1, 6-bisphosphate in hypoxic vascular smooth muscle [J]. Am J Physiol, 1994, 267(6 Pt 2): H2325-2332.
93. Lazzarino G, Hardin CD, Tavazzi B, et al. Myocardial metabolism of exogenous FDP is consistent with transport by a dicarboxylate transporter [J]. Am J Physiol Heart Circ Physiol, 2001, 281(6):H2654-2660.
94. Webb WR. Metabolic effects of fructose diphosphate in hypoxic and ischemic states [J]. J Thorac Cardiovasc Surg, 1984, 88(5 Pt 2):863-866.
95. 卢卫新, 戴瑞鸿. 1, 6-二磷酸果糖对组织缺血与缺氧的保护作用[J]. 中国临床医学, 2002, 9(1):91-92.
96. 张晶. 1,6-二磷酸果糖对缺血再灌注心肌的保护作用[J]. 中国循环杂志, 1991, 6(5):420.
97. Tavazzi B, Cerroni L, Di Pierro D, et al. Oxygen radical injury and loss of high-energy compounds in anoxic and reperfused rat heart: prevention by exogenous fructose-1,6-bisphosphate [J]. Free Radic Res Commun, 1990, 10(3):167-176.
98. Lazzarino G, Tavazzi B, Nuutinen M, et al. Protective effects of exogenously administered fructose-1,6-diphosphate from ischemia reperfusion damage induced on isolated rat heart [J]. Ital J Biochem, 1989, 38(4):251A-253A.
99. 赖平, 张洪泉, 马郁文, 等. 1, 6-二磷酸果糖对阿霉素心肌损伤防治作用的实验研究[J]. 山东医科大学学报, 1997, 35(3):242-244.
100. Cargnoni A, Condorelli E, Boraso A, et al. Role of timing of administration in the cardioprotective effect of fructose-1,6-bisphosphate [J]. Cardiovasc Drugs Ther, 1992, 6(3):209-217.
101. Hassinen IE, Nuutinen EM, Ito K,et al. Mechannism of the effect of Exogenous fructose 1, 6-bis-phosphateon myocardial energy metabolism [J]. Circulation, 1991,83(2) : 583-593.
102. Marchionni N, Conti A, De Alfieri W, et al. Hemodynamic and electrocardiographic effects of fructose-1,6-diphosphate in acute myocardial infarction [J]. Am J Cardiol, 1985, 56(4):266-269.
103. Daosukho C, Ittarat W, Lin SM, et al. Induction of manganese superoxide dismutase (MnSOD) mediates cardioprotective effect of tamoxifen (TAM) [J]. J Mol Cell Cardiol, 2005, 39(5):792-803.
104. Kaga S, Zhan L, Altaf E, et al. Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium [J]. J Mol Cell Cardiol, 2006, 40(1):138-147.
105. Fliss H, Gattinger D. Apoptosis in ischemic and reperfused rat myocardium [J]. Circ Res, 1996, 79(5):949-956.
106. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors [J]. N Engl J Med, 1997, 336(9):633-640.
107. Liu JL, LeRoith D. Insulin-like growth factor I is essential for postnatal growth in response to growth hormone [J]. Endocrinology, 1999, 140(11):5178-5184.
108. Ren J, Walsh MF, Hamaty M, et al. Altered inotropic response to IGF-I indiabetic rat heart: influence of intracellular Ca2+ and NO [J]. Am J Physiol, 1998, 275(3 Pt 2):H823-830.
109. Buerke M, Murohara T, Skurk C, et al. Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion [J]. Proc Natl Acad Sci U S A, 1995, 92(17):8031-8035.
110. Li Q, Li B, Wang X, et al. Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy [J]. J Clin Invest, 1997, 100(8):1991-1999.
111. Jonassen AK, Sack MN, Mjos OD, et al. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling [J]. Circ Res, 2001 Dec 7; 89(12):1191-1198.
112. Gao F, Gao E, Yue TL, et al. Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation [J]. Circulation, 2002, 105(12):1497-1502.
113. Zhao ZQ, Morris CD, Budde JM, et al. Inhibition of myocardial apoptosis reduces infarct size and improves regional contractile dysfunction during reperfusion [J]. Cardiovasc Res, 2003, 59(1):132-142.
114. Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger [J]. J Pharmacol Exp Ther, 1992, 263(1):92-98.
115. Yue TL, Ma XL, Wang X, et al. Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol [J].Circ Res, 1998, 82(2):166-174.
116. Packer M,Bristow MR,Cohn JN,et al.The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.New Eng1 J, Med. 1996, 334:1349-1397.
117. FeuersteinGZ, George P, Ruflolo RR, et al. Carvedilol updateⅢ: rational for use in congestive heart failure [J]. Drugs Today, 1995,31:307-326.
118. Kajstura J, Cigola E, Malhotra A, et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro [J]. J Mol Cell Cardiol, 1997, 29(3): 859-870.
119. Goussev A, Sharov VG, Shimoyama H, et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure [J]. Am J Physiol, 1998, 275(2 Pt 2): H626-631.
120. 石熠慧, 汤雪明. 细胞凋亡信号的传递途径及其调控[J]. 细胞生物学杂志, 1999, 21(2):49-54.
121. Webster KA, Discher DJ, Bishopric NH. Cardioprotection in an in vitro model of hypoxic preconditioning [J]. J Mol Cell Cardiol, 1995, 27(1):453-458.
122. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics [J]. Br J Cancer, 1972, 26(4):239-257.
123. Yang BC, Zander DS, Mehta JL. Hypoxia-reoxygenation-induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta (1) [J]. J Pharmacol Exp Ther, 1999 Nov; 291(2):733-738.
124. 徐德民, 赵强, 陈安清, 等. 缺氧诱导离体心肌细胞凋亡的动物实验研究[J]. 中国临床医学, 2004, 11(5):714-716.
125. Vermes I, Haanen C, Steffens-Nakken H, et al. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V [J]. J Immunol Methods, 1995, 184(1):39-51.
126. Ekhterae D, Lin Z, Lundberg MS, et al. ARC inhibits cytochrome c release from mitochondria and protects against hypoxia-induced apoptosis in heart-derived H9c2 cells [J]. Circ Res, 1999, 85(12):e70-77.
127. Liu X, Kim CN, Yang J, et al. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c [J]. Cell, 1996, 86(1):147-157.
128. 张莉莉, 林久治, 蔡玲玲. 围产儿缺氧缺血性脑病 124 例的临床及病理学研究[J]. 中华妇产科杂志, 1996, 31(2):100-102.
129. 陈惠金, 周建德, 周泽汉, 等. 新生大鼠脑缺氧缺血损伤模型的制备[J]. 上海实验动物科学, 1999, 19(3):159-160.
130. Meade HM, Heading CE, Ball SJ. Glycylproline absorption in rats infected with Eimeria nieschulzi [J]. Biochem Soc Trans, 1981, 9(1):131-132.
131. Renolleau S, Aggoun-Zouaoui D, Ben-Ari Y, et al. A model of transient unilateral focal ischemia with reperfusion in the P7 neonatal rat: morphological changes indicative of apoptosis [J]. Stroke, 1998, 29(7):1454-1460.
132. 吴蓉洲, 李伟, 吴起朝, 等. 血清心肌肌钙蛋白-Ⅰ对新生儿窒息心肌损伤的诊断价值探讨[J]. 中国实用儿科杂志, 2000, 15(2):114.
133. 白希莲, 韩玉昆, 徐长新. 足月新生儿窒息后心功能的早期评价[J]. 中国实用儿科, 1994, 9(2):93-95.
134. 娜淇, 方幼萍, 王明中, 等. 乳酸脱氢酶同功酶测定对窒息新生儿缺氧损伤的评价[J]. 中国实用儿科杂志, 1994, 9(2):100-101.
135. 时锋, 许雯, 顾芳香. 新生儿窒息后心肌损害的评价[J]. 医学理论与实践, 2000, 13(9):560-561.
136. 池美珠, 陆中权. 新生儿窒息及脑损伤后心肌损害的研究[J]. 中国当代儿科杂志, 2000, 2(1):51-52.
137. Wijsman JH, Jonker RR, Keijzer R, et al. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA [J]. J Histochem Cytochem, 1993, 41(1):7-12.
138. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation [J]. J Cell Biol, 1992, 119(3):493-501.
139. Lim ML, Lum MG, Hansen TM, et al. On the release of cytochrome c from mitochondria during cell death signaling [J]. J Biomed Sci, 2002, 9(6 Pt 1): 488-506.
140. Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis [J]. J Cell Biol, 2003,160(1):65-75.
141. Kiechle FL, Zhang X. Apoptosis: biochemical aspects and clinical implications [J]. Clin Chim Acta, 2002, 326(1-2):27-45.
142. Higuchi M, Aggarwal BB, Yeh ET. Activation of CPP32-like protease in tumor necrosis factor-induced apoptosis is dependent on mitochondrial function [J]. J Clin Invest, 1997, 99(7):1751-1758.
143. Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis [J]. Nat Med, 1997, 3(6):614-620.
144. Gross A, Jockel J, Wei MC, et al. Enforced dimerization of BAX results inits translocation, mitochondrial dysfunction and apoptosis [J]. EMBO J, 1998, 17(14):3878-3885.
145. Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked [J]. Science, 1997, 275(5303): 1129-1132.
146. Zhan Q, Fan S, Bae I, et al. Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis. Oncogene 1994;9(12): 3743-51.
147. Ballot DE, Rothberg AD, Davies VA, et al. Does hypoxemia prevent brain damage in birth asphyxia [J]? Med Hypotheses, 1993, 41(4):344-347.
148. Raha S, Robinson BH. Mitochondria, oxygen free radicals, and apoptosis [J]. Am J Med Genet, 2001, 106(1):62-70.
149. Turner NA, Xia F, Azhar G, et al. Oxidative stress induces DNA fragmentation and caspase activation via the c-Jun NH2-terminal kinase pathway in H9c2 cardiac muscle cells [J]. J Mol Cell Cardiol, 1998, 30(9): 1789-1801.
150. 李笑天, 潘明明, 庄依亮, 等. 胎儿缺氧和酸中毒对超氧化物歧化酶水平的影响[J]. 中华妇产科杂志, 2002, 37(4): 205-207.
151. 郑大同, 李述庭, 高雁翎, 等. 新生鼠缺氧缺血性脑损伤组织一氧化氮合酶基因表达及作用[J]. 中华儿科杂志, 2001, 39 (1):44.
152. Mery PF, Lohmann SM, Walter U, et al. Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes [J]. Proc Natl Acad Sci USA, 1991, 88(4):1197-201.
153. 黄忠耀, 朱洪生, 张有荣, 等. 卡托普利心脏停搏液对缺血再灌注心肌NOS 活性和 NO 产生的影响[J]. 中华胸心血管外科杂志, 1999, 15(3): 182-184.