促红细胞生成素对急性心肌缺血再灌注后大鼠心肌凋亡基因的实验研究
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摘要
目的:人们往往使用再灌注疗法恢复缺血心肌细胞的血流供应。心肌细胞凋亡在心肌缺血再灌注损伤中普遍存在,并且是缺血再灌注早期心肌细胞死亡的主要方式。在心肌缺血再灌注损伤发病机制中,细胞凋亡可能是再灌注损伤的重要组成部分之一,而且凋亡在特定阶段前的干预部分是可逆的。研究再灌注损伤时心肌细胞抗凋亡机制可以提供一个潜在的方法来减轻再灌注诱导的细胞凋亡。
近年来,人们认识到重组人促红细胞生成素(recombinant human erythropoietin, EPO)在心血管疾病中的重要作用。Calvillo等在培养的大鼠心肌细胞缺氧损伤实验中发现,应用EPO的细胞凋亡率降低50%,证实EPO具有抗心肌细胞凋亡的作用。但是EPO对凋亡基因的研究尚不太清楚。Bcl-2蛋白基因家族是控制凋亡的关键基因,包括抗凋亡基因Bcl-2和促凋亡基因Bax,但是EPO是否通过Bcl-2、Bax发挥抗凋亡作用尚不清楚,研究Bcl-2蛋白基因家族有助于进一步了解EPO的抗凋亡作用。研究发现血管内皮生长因子(vascular endothelial growth factor,VEGF)的表达,可能使血管新生更容易,远期可以减少心肌细胞的凋亡。VEGF产生的这种效应的机制也可能是升高抗凋亡蛋白Bcl-2的表达,降低促凋亡蛋白Bax的表达,从而减少细胞凋亡。因此,EPO可能是通过影响Bcl-2、Bax蛋白及基因的表达,从而抑制细胞凋亡,达到改善急性心肌缺血再灌注后心脏功能的作用。
本实验通过建立大鼠心肌缺血再灌注模型,应用EPO观察Bcl-2蛋白,Bax蛋白,VEGF蛋白表达及Bcl-2mRNA、BaxmRNA表达,来探讨促红细胞生成素的心脏保护作用。
方法:健康雄性Sprague Dawley大鼠54只,清洁级,12-15周龄,体重210-260g,平均225g,阻断大鼠左冠状动脉前降支建立大鼠急性心肌缺血再灌注模型,随机分为3组,假手术组(Sham组)、缺血再灌注对照组(IR组)和EPO组(EPO,EPO 3000U/kg/d共3天)。应用免疫组化方法测定Bcl-2、Bax蛋白及VEGF蛋白表达,应用RT-PCR方法测定Bcl-2mRNA、BaxmRNA。数据采用SPSS 17.0统计软件处理,组间比较采用单因素方差分析,两两比较采用q检验。
结果:(1)EPO对大鼠边缘区心肌细胞Bcl-2蛋白表达的影响:与Sham组相比较,IR组、EPO组Bcl-2蛋白表达在48h、2w、3w均显著降低,有统计学意义。与IR组相比较,EPO组Bcl-2蛋白表达在48h、2w、3w均增高,分别增高27.7%、31.4%、25.9%(均P<0.01)。(2)EPO对大鼠边缘区心肌细胞Bax蛋白表达的影响:与Sham组相比较,IR组、EPO组Bax蛋白表达在48h、2w、3w均显著增高,有统计学意义。与IR组相比较,EPO组Bax蛋白表达在48h、2w、3w均降低,分别降低20.9%、18.0%、16.7%(均P<0.01)。(3)EPO对大鼠边缘区心肌细胞Bcl-2/Bax蛋白表达的影响:与Sham组相比较,IR组、EPO组Bcl-2/Bax比值在各时间点均显著降低(均P<0.05)。与IR组相比较,EPO组Bcl-2/Bax比值在各时间点均显著增高(均P<0.05)。(4)EPO对大鼠边缘区心肌细胞Bcl-2mRNA表达的影响:与Sham组相比较,IR组、EPO组Bcl-2mRNA表达在48h、2w、3w均显著降低,有统计学意义。与IR组相比较,EPO组Bcl-2mRNA表达在48h、2w、3w均增高,分别增高61.0%、32.7%、39.9%(P<0.01)。(5)EPO对大鼠边缘区心肌细胞表达的影响:与Sham组相比较,BaxmRNA、EPO组BaxmRNA表达在48h、2w、3w均显著增高,有统计学意义。与IR组相比较,EPO组BaxmRNA表达在48h、2w、3w均降低,分别降低11.4%、7.7%、34.2%(P<0.01)。(6)EPO对大鼠边缘区心肌细胞Bcl-2/BaxmRNA表达的影响:与Sham组相比较,IR组、EPO组Bcl-2/BaxmRNA比值在各时间点均显著降低(P<0.05)。与IR组相比较,EPO组Bcl-2/BaxmRNA比值在各时间点均显著增高( P<0.05)。(7)EPO对大鼠边缘区心肌细胞VEGF蛋白表达的影响:与Sham组相比较,IR组、EPO组VEGF蛋白表达在48h、2w、3w均显著增高,有统计学意义。与IR组相比较,EPO组VEGF蛋白表达在48h、2w、3w均增高,分别增高22.1%、21.4%、20.5%(P<0.01 or P<0.05)。
结论:(1)大鼠急性心肌缺血再灌注后边缘区心肌细胞Bcl-2蛋白及mRNA的低表达,Bax蛋白及mRNA的高表达。(2)EPO在大鼠缺血再灌注后可增加边缘区心肌Bcl-2蛋白、VEGF蛋白及mRNA的表达,降低Bax蛋白及mRNA的表达,增高Bcl-2/Bax的比值。表明了EPO可能通过调节Bcl-2、Bax的表达而抑制缺血再灌注损伤,减少细胞凋亡,产生对心脏的保护作用。
Objective: It is often used reperfusion therapy to recover the blood supply of the ischaemic myocardial cell. Myocardial cell apoptosis in myocardial ischemia-reperfusion injury is very common, and apoptosis is the main deadly forms in the early stage of ischemia-reperfusion. Studying the anti-apoptosis mechanisms after ischemia-reperfusion could provide a potential way to reduce the apoptosis induced by reperfusion.
In recent years, it is recognized the important role of EPO(recombinant human erythropoietin) in cardiovascular diseases. Calvillo found that adding EPO in cultured hypoxic injury rat myocardial cells, apoptosis decreased by 50% and confirmed that EPO has the anti- apoptosis function. But the EPO on apoptosis genes is less clear. Bcl-2 protein gene family is critical in apoptosis genes, include anti-apoptosis gene Bcl-2 and pro-apoptosis gene Bax,but it is not clear that the anti-apoptosis function of EPO is created via Bcl-2 protein gene family, so studying the Bcl-2 protein gene family is helpful for explaining the protecting function of EPO. Study found that the expression of VEGF (vascular endothelial growth factor) may make it easier to angiogenesis, and can reduce long term myocardial cell apoptosis. The mechanisms of VEGF may increase the expression of anti-apoptotic protein Bcl-2, reduce the expression of pro-apoptotic protein Bax, thereby reducing apoptosis. So EPO inhibit apoptosis may be by influencing Bcl-2 protein family, and then improve the cardiac function after acute myocardial ischemia-reperfusion.
In this study, a animal model of IR(ischemia-reperfusion) was used, and followed treatment with recombinant human EPO (EPO). The expression of Bcl-2 protein, Bax protein, VEGF protein, Bcl-2 mRNA, Bax mRNA were obtained after IR, and then to investigate the protective mechanismss of EPO.
Methods: 54 healthy male Sprague Dawley rats (12-15 weeks and 210-260g) were recruited. Rat models of IR were induced by blocking left anterior decending coronary artery. The 54 rats were divided into 3 groups randomly: sham-operated group, IR group and EPO group (recombinant human EPO 3000U·kg-1·d-1 intraperitoneal injection, for 3 days). The Bcl-2 protein, Bax protein, VEGF protein, were quantified by immunohistochemical method. RT-PCR was used to observe the gene expression of Bcl-2 mRNA, Bax mRNA. All data were analyzed with SPSS version 17.0 statistical software. The comparison among groups was analyzed by One-Way ANOVA and S-N-K test.
Results: (1) The effect of EPO on the expression of Bcl-2 protein in border areas: Compared with sham-operated group, the expression of Bcl-2 protein detected in border areas significantly decreased in IR group and EPO group at 48h, 2w and 3w (P<0.01); Compared with IR group, the expression of Bcl-2 protein detected in border areas raised 27.7%, 31.4%, 25.9% respectively in EPO group at 48h, 2w and 3w (P<0.01). (2) The effect of EPO on the expression of Bax protein in border areas: Compared with sham-operated group, the expression of Bax protein detected in border areas significantly increased raised in IR group and EPO group at 48h(P<0.01); Compared with IR group, the expression of Bax protein detected in border areas lowered 20.9%, 18.0%, 16.7% respectively in EPO group at 48h, 2w and 3w (P<0.01). (3) The effect of EPO on the ratio of Bcl-2 and Bax protein in border areas: Compared with sham-operated group, the ratio of Bcl-2 and Bax protein was significantly decreased in IR group and EPO group at the different time (P<0.05); Compared with IR group, the ratio of Bcl-2 and Bax protein was in EPO group at the different time (P<0.05); (4) The effect of EPO on the expression of Bcl-2mRNA in border areas: Compared with sham-operated group, the expression of Bcl-2mRNA detected in border areas decreased in IR group and EPO group at 48h, 2w and 3w (P<0.01); Compared with IR group, the expression of Bcl-2mRNA detected in border areas raised 61.0%, 32.7%, 39.9% respectively in EPO group at 48h, 2w and 3w (P<0.01). (5) The effect of EPO on the expression of BaxmRNA in border areas: Compared with sham-operated group, the expression of BaxmRNA detected in border areas significantly increased in IR group and EPO group at 48h, 2w and 3w (P<0.01); Compared with IR group, the expression of BaxmRNA detected in border areas lowered 11.4%, 7.7%, 34.2% respectively in EPO group at 48h, 2w and 3w (P<0.01).(6) The effect of EPO on the ratio of Bcl-2 and Bax mRNA in border areas: Compared with sham-operated group, the ratio of Bcl-2 and Bax mRNA was significantly decreased in IR group and EPO group at the different time (P<0.05); Compared with IR group, the ratio of Bcl-2 and Bax mRNA was significantly increased in EPO group at the different time (P<0.05); (7) The effect of EPO on the expression of VEGF protein in border areas: Compared with sham-operated group, the expression of VEGF protein detected in border areas significantly increased in IR group and EPO group at 48h, 2w and 3w; (P<0.01 or P<0.05); Compared with IR group, the expression of VEGF protein detected in border areas raised 22.1%, 21.4%, 20.5% respectively in EPO group at 48h, 2w and 3w (P<0.01).
Conculsion:(1) This study showed that the lower expression of Bcl-2 protein and mRNA, higher expression of Bax protein and mRNA in border areas after myocardial ischemia-reperfusion. (2) EPO could increase the expression of Bcl-2 protein ,VEGF protein and Bcl-2 mRNA, reduce the expression of Bax protein and Bax mRNA, increase the ratio of Bcl-2/Bax in border areas after myocardial ischemia-reperfusion. It is possible that EPO may bring cardiac protective function by regulateing the expression of Bcl-2 and Bax to inhibit the ischemia-reperfusion injury.
近年来,人们认识到重组人促红细胞生成素(recombinant human erythropoietin, EPO)在心血管疾病中的重要作用。Calvillo等在培养的大鼠心肌细胞缺氧损伤实验中发现,应用EPO的细胞凋亡率降低50%,证实EPO具有抗心肌细胞凋亡的作用。但是EPO对凋亡基因的研究尚不太清楚。Bcl-2蛋白基因家族是控制凋亡的关键基因,包括抗凋亡基因Bcl-2和促凋亡基因Bax,但是EPO是否通过Bcl-2、Bax发挥抗凋亡作用尚不清楚,研究Bcl-2蛋白基因家族有助于进一步了解EPO的抗凋亡作用。研究发现血管内皮生长因子(vascular endothelial growth factor,VEGF)的表达,可能使血管新生更容易,远期可以减少心肌细胞的凋亡。VEGF产生的这种效应的机制也可能是升高抗凋亡蛋白Bcl-2的表达,降低促凋亡蛋白Bax的表达,从而减少细胞凋亡。因此,EPO可能是通过影响Bcl-2、Bax蛋白及基因的表达,从而抑制细胞凋亡,达到改善急性心肌缺血再灌注后心脏功能的作用。
本实验通过建立大鼠心肌缺血再灌注模型,应用EPO观察Bcl-2蛋白,Bax蛋白,VEGF蛋白表达及Bcl-2mRNA、BaxmRNA表达,来探讨促红细胞生成素的心脏保护作用。
方法:健康雄性Sprague Dawley大鼠54只,清洁级,12-15周龄,体重210-260g,平均225g,阻断大鼠左冠状动脉前降支建立大鼠急性心肌缺血再灌注模型,随机分为3组,假手术组(Sham组)、缺血再灌注对照组(IR组)和EPO组(EPO,EPO 3000U/kg/d共3天)。应用免疫组化方法测定Bcl-2、Bax蛋白及VEGF蛋白表达,应用RT-PCR方法测定Bcl-2mRNA、BaxmRNA。数据采用SPSS 17.0统计软件处理,组间比较采用单因素方差分析,两两比较采用q检验。
结果:(1)EPO对大鼠边缘区心肌细胞Bcl-2蛋白表达的影响:与Sham组相比较,IR组、EPO组Bcl-2蛋白表达在48h、2w、3w均显著降低,有统计学意义。与IR组相比较,EPO组Bcl-2蛋白表达在48h、2w、3w均增高,分别增高27.7%、31.4%、25.9%(均P<0.01)。(2)EPO对大鼠边缘区心肌细胞Bax蛋白表达的影响:与Sham组相比较,IR组、EPO组Bax蛋白表达在48h、2w、3w均显著增高,有统计学意义。与IR组相比较,EPO组Bax蛋白表达在48h、2w、3w均降低,分别降低20.9%、18.0%、16.7%(均P<0.01)。(3)EPO对大鼠边缘区心肌细胞Bcl-2/Bax蛋白表达的影响:与Sham组相比较,IR组、EPO组Bcl-2/Bax比值在各时间点均显著降低(均P<0.05)。与IR组相比较,EPO组Bcl-2/Bax比值在各时间点均显著增高(均P<0.05)。(4)EPO对大鼠边缘区心肌细胞Bcl-2mRNA表达的影响:与Sham组相比较,IR组、EPO组Bcl-2mRNA表达在48h、2w、3w均显著降低,有统计学意义。与IR组相比较,EPO组Bcl-2mRNA表达在48h、2w、3w均增高,分别增高61.0%、32.7%、39.9%(P<0.01)。(5)EPO对大鼠边缘区心肌细胞表达的影响:与Sham组相比较,BaxmRNA、EPO组BaxmRNA表达在48h、2w、3w均显著增高,有统计学意义。与IR组相比较,EPO组BaxmRNA表达在48h、2w、3w均降低,分别降低11.4%、7.7%、34.2%(P<0.01)。(6)EPO对大鼠边缘区心肌细胞Bcl-2/BaxmRNA表达的影响:与Sham组相比较,IR组、EPO组Bcl-2/BaxmRNA比值在各时间点均显著降低(P<0.05)。与IR组相比较,EPO组Bcl-2/BaxmRNA比值在各时间点均显著增高( P<0.05)。(7)EPO对大鼠边缘区心肌细胞VEGF蛋白表达的影响:与Sham组相比较,IR组、EPO组VEGF蛋白表达在48h、2w、3w均显著增高,有统计学意义。与IR组相比较,EPO组VEGF蛋白表达在48h、2w、3w均增高,分别增高22.1%、21.4%、20.5%(P<0.01 or P<0.05)。
结论:(1)大鼠急性心肌缺血再灌注后边缘区心肌细胞Bcl-2蛋白及mRNA的低表达,Bax蛋白及mRNA的高表达。(2)EPO在大鼠缺血再灌注后可增加边缘区心肌Bcl-2蛋白、VEGF蛋白及mRNA的表达,降低Bax蛋白及mRNA的表达,增高Bcl-2/Bax的比值。表明了EPO可能通过调节Bcl-2、Bax的表达而抑制缺血再灌注损伤,减少细胞凋亡,产生对心脏的保护作用。
Objective: It is often used reperfusion therapy to recover the blood supply of the ischaemic myocardial cell. Myocardial cell apoptosis in myocardial ischemia-reperfusion injury is very common, and apoptosis is the main deadly forms in the early stage of ischemia-reperfusion. Studying the anti-apoptosis mechanisms after ischemia-reperfusion could provide a potential way to reduce the apoptosis induced by reperfusion.
In recent years, it is recognized the important role of EPO(recombinant human erythropoietin) in cardiovascular diseases. Calvillo found that adding EPO in cultured hypoxic injury rat myocardial cells, apoptosis decreased by 50% and confirmed that EPO has the anti- apoptosis function. But the EPO on apoptosis genes is less clear. Bcl-2 protein gene family is critical in apoptosis genes, include anti-apoptosis gene Bcl-2 and pro-apoptosis gene Bax,but it is not clear that the anti-apoptosis function of EPO is created via Bcl-2 protein gene family, so studying the Bcl-2 protein gene family is helpful for explaining the protecting function of EPO. Study found that the expression of VEGF (vascular endothelial growth factor) may make it easier to angiogenesis, and can reduce long term myocardial cell apoptosis. The mechanisms of VEGF may increase the expression of anti-apoptotic protein Bcl-2, reduce the expression of pro-apoptotic protein Bax, thereby reducing apoptosis. So EPO inhibit apoptosis may be by influencing Bcl-2 protein family, and then improve the cardiac function after acute myocardial ischemia-reperfusion.
In this study, a animal model of IR(ischemia-reperfusion) was used, and followed treatment with recombinant human EPO (EPO). The expression of Bcl-2 protein, Bax protein, VEGF protein, Bcl-2 mRNA, Bax mRNA were obtained after IR, and then to investigate the protective mechanismss of EPO.
Methods: 54 healthy male Sprague Dawley rats (12-15 weeks and 210-260g) were recruited. Rat models of IR were induced by blocking left anterior decending coronary artery. The 54 rats were divided into 3 groups randomly: sham-operated group, IR group and EPO group (recombinant human EPO 3000U·kg-1·d-1 intraperitoneal injection, for 3 days). The Bcl-2 protein, Bax protein, VEGF protein, were quantified by immunohistochemical method. RT-PCR was used to observe the gene expression of Bcl-2 mRNA, Bax mRNA. All data were analyzed with SPSS version 17.0 statistical software. The comparison among groups was analyzed by One-Way ANOVA and S-N-K test.
Results: (1) The effect of EPO on the expression of Bcl-2 protein in border areas: Compared with sham-operated group, the expression of Bcl-2 protein detected in border areas significantly decreased in IR group and EPO group at 48h, 2w and 3w (P<0.01); Compared with IR group, the expression of Bcl-2 protein detected in border areas raised 27.7%, 31.4%, 25.9% respectively in EPO group at 48h, 2w and 3w (P<0.01). (2) The effect of EPO on the expression of Bax protein in border areas: Compared with sham-operated group, the expression of Bax protein detected in border areas significantly increased raised in IR group and EPO group at 48h(P<0.01); Compared with IR group, the expression of Bax protein detected in border areas lowered 20.9%, 18.0%, 16.7% respectively in EPO group at 48h, 2w and 3w (P<0.01). (3) The effect of EPO on the ratio of Bcl-2 and Bax protein in border areas: Compared with sham-operated group, the ratio of Bcl-2 and Bax protein was significantly decreased in IR group and EPO group at the different time (P<0.05); Compared with IR group, the ratio of Bcl-2 and Bax protein was in EPO group at the different time (P<0.05); (4) The effect of EPO on the expression of Bcl-2mRNA in border areas: Compared with sham-operated group, the expression of Bcl-2mRNA detected in border areas decreased in IR group and EPO group at 48h, 2w and 3w (P<0.01); Compared with IR group, the expression of Bcl-2mRNA detected in border areas raised 61.0%, 32.7%, 39.9% respectively in EPO group at 48h, 2w and 3w (P<0.01). (5) The effect of EPO on the expression of BaxmRNA in border areas: Compared with sham-operated group, the expression of BaxmRNA detected in border areas significantly increased in IR group and EPO group at 48h, 2w and 3w (P<0.01); Compared with IR group, the expression of BaxmRNA detected in border areas lowered 11.4%, 7.7%, 34.2% respectively in EPO group at 48h, 2w and 3w (P<0.01).(6) The effect of EPO on the ratio of Bcl-2 and Bax mRNA in border areas: Compared with sham-operated group, the ratio of Bcl-2 and Bax mRNA was significantly decreased in IR group and EPO group at the different time (P<0.05); Compared with IR group, the ratio of Bcl-2 and Bax mRNA was significantly increased in EPO group at the different time (P<0.05); (7) The effect of EPO on the expression of VEGF protein in border areas: Compared with sham-operated group, the expression of VEGF protein detected in border areas significantly increased in IR group and EPO group at 48h, 2w and 3w; (P<0.01 or P<0.05); Compared with IR group, the expression of VEGF protein detected in border areas raised 22.1%, 21.4%, 20.5% respectively in EPO group at 48h, 2w and 3w (P<0.01).
Conculsion:(1) This study showed that the lower expression of Bcl-2 protein and mRNA, higher expression of Bax protein and mRNA in border areas after myocardial ischemia-reperfusion. (2) EPO could increase the expression of Bcl-2 protein ,VEGF protein and Bcl-2 mRNA, reduce the expression of Bax protein and Bax mRNA, increase the ratio of Bcl-2/Bax in border areas after myocardial ischemia-reperfusion. It is possible that EPO may bring cardiac protective function by regulateing the expression of Bcl-2 and Bax to inhibit the ischemia-reperfusion injury.
引文
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11 Cagli k,Bagci C, Gulec M,et al.In vivo effects of caffeic acid phenethylester on myocardial ischemia-reperfusion injury and apoptotic changes in rats. Ann Clin Lab Sci, 2005,35(4):440-448
12 Emily H.-Y. A. Cheng, Michael C. Wei, Solly Weiler, et al. BCL-2, BCL-XL Sequester BH3 Domain-Only Molecules Preventing BAX- and BAK-Mediated Mitochondrial Apoptosis. Molecular Cell, 2001, 8, 705-711
13 Formigli L, Ibba-Manneschi L, Perna AM, et al. Ischemia-reperfusion-induced apoptosis and p53 expression in the course of rat heterotopic heart transplantation. Microvasc Res. 1998, 56(3): 277-281
14叶亮,杜心灵,夏家红等。重组人红细胞生成素对心肌梗死治疗作用的实验研究。中华医学杂志。2006,86:2776-2780
15 Tramontano AF, Muniyappa R, Black AD, et al. Erythropoietin protects cardiacmyocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun, 2003, 308(4): 990-994
16 Cai Z, Manalo DJ, wei G, et al. Hearts from rodents exposed to inter mittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation, 2003, 108(1): 79-85
17 Jun Yang, YuanGui Huang, Xin Yu, et al. Erythropoietin preconditioning supresses neuronal death following status epilepticus in rats. Acta Neurobiol Exp, 2007, 67: 141-148
18 Van der Meer P, Lipsic E, Henning RH, et al. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury. Eur J Heart Fail, 2004, 6(7): 853-859
19 Vincenti V, Cassano C, Rocchi M, et al. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation, 1996, 93(8): 1493-1495
20 Zachary I, Mathur A, Yla-Herttuala S, et al. Vascular protection: A novel nonangiogenic cardiovasular role for vascular endothelial growth factor. Arterioscler Thromb Vasc Biol, 2000, 20(6): 1512-1520
21 Servos S, Zachary I, Martin JF, et al. VEGF modulates NO production: the basis of a cytoprotective effect?. Cardiovasc Res, 1999, 41(3): 509-510
22 Ware JA, simons M, et al. Angiogenesis in ischemic heart disease. Nature Med, 1997, 3(2): 158-164
23 JW Yockman, D Choi, MG Whitten, et al. Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct. Gene Therapy, 2009, 16, 127-135
24 Yau TM, Kim C, Li G, et al. Maximizing ventricular function with multimodal cell-based fene therapy. Circulation, 2005, 112:I123-I128
25 Yoon YS, Uchida S, Masuo O. Progressive attenuation of myocardial vasular endothelial growth factor expression is a seminal event in diabetic cardiomypathy: Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation, 2005, 111: 2073-2085
26 Ruixing Y, Jiaquan L, Jie C, et al. Intravenous administration of vascular endothelial growth factor improves cardiac performance and inhibits cardiomyocyte apoptosis. Growth Factors, 2006, 24(3): 209-217
27 Ruixing Y, Dezhai Y, Hai W, et al. Intramyocardial injection of vascular endothelial growth factor gene improves cardiac performance and inhibits cardiomyocyte apoptosis. Eur J Heart Fail, 2007, 9(4): 343-351
28 Hiroaki Sasaki, Shoji Fukuda, Hajime Otani, et al. Hypoxic Preconditioning Triggers Myocardial Angiogenesis: a Novel Approach to Enhance Contractile Functional Reserve in Rat with Myocardial Infarction. Mol Cell Cardiol, 2002,34, 335-348
29 Gerber HP, Mcmurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates cell survival through the phosphatidylinositol 3′-Kinase/Akt signal transduction pathway. Biol Chem, 1998, 273: 46: 30336-30343
30 Uemura R, Xu M, Ahmad N, et al. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res, 2006, 98: 1414-1421
31 Xu M, Uemura R, Dai Y, et al. In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. Mol Cell Cardiol, 2007, 42: 441- 448
1 Elmore S, et al. Apoptosis: a review of programmed cell death. Toxicol pathol, 2007, 35(4):495-516
2 Piper HM, Meuter K, Schafer C, et al. Cellular mechanismss of ischemia-reperfusion injury. Ann Thorac Surg, 2003, 75(2): S644-648
3谢俊然,郁丽娜,段世明.心肌缺血再灌注损伤心肌细胞凋亡的分子调节机制。国外医学麻醉学与复苏分册,2005,26(4):226-228
4 Yellon DM, Hausenloy DJ, et al. Myocardial reperfusion injury. N Engl J Med. 2007; 357(11): 1121-1135
5孙涛,苏全生。自由基与心肌缺血/再灌注损伤。实用医院临床杂志,2006,3 (4):94-96
6 Zhang C, Xu X, Potter B J, et al. TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol, 2006, 26 (3): 475-480
7 Kim JK, Pedram A, RazandiM, et al. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem, 2006, 281 (10) : 6760-6767
8 Petrosillo G, Ruggiero FM, Divenosa N, et al. Decreased complexIII activity in mitochondria isolated from rat heart subjected to ischemia and reperfusion: role of reactive oxygen species and cardiolipin. FAS EB J , 2003, 17 (6): 714-716
9 Nordlie MA, Wold LE, Simkhovich BZ, et al. Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy. J Cardiovasc Pharmacol Ther, 2006, 11 (1): 17-30
10 Vempati UD, Diaz F, Barrientos A, et al. Role of cytochrome C in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but notwith lack of cytochrome C release. Mol Cell Biol, 2007, 27(5): 1771-1783
11 Belizario JE, Alves J, Occhiucci JM, et al. A mechanistic view of mitochondrial death decision pores. Braz J Med Biol Res, 2007, 40(8): 1011-1024
12 Wang J, Zhang Z, Hu Y, et al. SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse vetricular myocytes. Physiol Res, 2007, 56(1): 17-23
13 Agocha A, Lee HW, et al. Hhpoxia regulates basal and induced DNA synthesis and collagen typeⅠproduction in human cardiac fibrobrasts: effects of transforming growth factor-β1, thyroid hormone, angiotensin II and basic fibrobrasts growth factor. J Mol Cell Cardiol, 1997, 29 (8): 2233-2244
14 Haudek SB, Taffet GE, Schneider MD, et al. TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest, 2007, 117 (9): 2692-2701
15 Dhingra S, Sharma A K, Singla D K, et al. P38 and ERK1/2 MAPKs mediate the interplay of TNF-alpha and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol, 2007, 293 (6) : 3524-3531
16 Braithwaite AW, Prives CL, et al. P53: more research and more questions. Cell Death Differ 2006, 13(6): 877-880
17 Alvarez S, Drane P, Meiller A, et al. A comprehensive study of p53 transcriptional activity in thymus and spleen of gamma irradiated mouse: High sensitivity of genes involved in the two main apoptotic pathways. Int J Radiat Biol 2006; 82(11): 761-770
18 Wang DS, Li Y, Dou KF, et al. Utility of adenovirus-mediated Fas ligand and bcl-2 gene transfer to modulate rat liver allograft survival. Hepatobiliary Pancreat Dis Int, 2006, 5(4): 505-510
19 Du C, Wang S, Diao H, et al. Increasing resistance of tubular epithelial cells to apoptosis by shRNA therapy ameliorates renal ischemia-reperfusion injury. Am J Transplant, 2006, 6 (10): 2256-2267
20 Davidson SM, Hausenloy D, Duchen MR, et al. Signalling via thereperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem cell Biol. 2006, 38 (3): 414-419
21 Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, et al. Stimulation of the stress activated mitogen-activated protein kinase subfamilies in perfused heart, p38/RK mitogen- activated protein kinasesand c-Jun N- terminal kinases are activated by ischemia/reperfusion. Circ Res, 1996, 79: 162-173
22 MOOSAVIM A, YAZDANPARAST R, LOTFI A, et al. ERK1/2 inactivation and p38 MAPK-dependent caspase activation during guanosine 5’-triphosphate-mediated terminal erythroid differentiation of K562 cells. Int J Biochem Cell Biol, 2007, 39(9): 1685-1697
23 Li Z, Ma JY, Kerr I, et al. Selective inhibition of p38α-MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. Am J Physiol Heart Circ Physiol, 2006, 291(4): H1 972-H1977
24 Negoro S, Kunisada K, Tone E, et a1. Activation of JAK/STAT pathway transduces cytop rotective signal in rat acute myocardial infarction. Cardiovasc Res, 2000, 47 (4) : 797-805
25 Li D, Williams V, Liu L, et al. Expression of lectin-like oxidized low density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. J Am Coll Cardiol, 2003, 41 (6): 1048-1055
26 Hayashida K, Kume N, Murase T, et al. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome: a novel marker for early diagnosis. Circulation 2005, 112(6): 812- 818
27 Kadota J, Mizunoe S, Mukae H, et al. The expression of pro-and anti-apoptotic Bcl-2 family proteins in peribronchiolar lymphocytes from patients with diffuse panbronchiolitis. Respiratory Medicine, 2006, 100 (11): 2029-2036
28 Yildirim E, Ozisik K, Ozisik P, et al. Apoptosis-related gene Bcl-2 in lung tissue after experimental traumatic brain injury in rats. Heart, Lung & Circulation, 2006, 15 (2): 124-129
29 Hajnoczky G, Csordas G, Das S, et al. Mitochondrial calcium signalling and cell death: approaches for as sessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium, 2006; 40(5-6): 553-560
30 Lu G, Kang YJ, Han J, et al. TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J Biol Chem, 2006, 281 (9): 6087 - 6095
31 Zhang H, et al. P53 plays a central role in UVA and UVB induced cell damage and apoptosis in melanoma cells. Cancer Lett, 2006, 244 (2): 229-238
32 Pelengaris S, Khan M, et al. The many faces of c-MYC. Arch Biochem Biophysics, 2003, 416 (2): 129-136
33 Zhuang WJ, Fong CC, Cao J, et al. Involvement of NF-κB and c-myc signaling pathways in the apoptosis of HL-60 cells induced by alkaloids of Tripterygium hypoglaucum (levl.)Hutch. Phytomedicine, 2004, 11 (4): 295-302
34 Nelson DP, Wechsler SB, Miura T, et al. Myocardial immediate early gene activation after cardiopulmonary bypass with cardiac ischemia reperfusion. Ann Thorac Surg, 2002, 73 (1): 156-162
35 Yang J, Marden JJ, Fan C, et al. Genetic redox preconditioning differentially modulates AP-1 and NF-kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis. Mol Ther, 2003, 7 (3) : 341-353
36 Kobara M, Tatsumi T, et al. Effects of ACE inhibition on myocardial apoptosis in an ischemia-reperfusion rat heart model. J Cardiovasc Pharmacol, 2003, 41 (6): 880-889
37 Parlakp inarH, Sahna E, et al. Protective effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia-reperfusion-induced apoptotic cell death. Toxicology, 2005, 209 (1): 1-14
38 Fu J, Lin G, Wu Z, et al. Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury. Biochem Biophys Res Commun. 2006, 349(2): 504-512
39 Liu HR, Gao F, et al. Antiapoptotic mechanismss of benidipine in the ischemic/reperfused heart. Br J Pharmacol, 2004, 142 (4) : 627-634
40 Satwani S , Dec GW, Narula J, et al. Beta-adrenergic blockers in heart failure: review of mechanismss of action and clinical outcomes. J Cardiovasc Pharmacol Ther, 2004; 9: 243-255
2 Fliss H, Gattinger D, et al. Apoptosis in ischemic and reperfused rat myocardium. Circ Res, 1996, 79(5): 949-956
3 Patel NS, Sharples EJ, Cuzzocrea S, et al. Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int 2004, 66: 983–989.
4 Daisuke Nishiya1, Takashi Omura1, Kenei Shimada, et al. Effects of Erythropoietin on Cardiac Remodeling After Myocardial Infarction. J Pharmacol Sci. 2006, 101: 31-39
5 Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA. 2003, 100: 4802-4806
6 Danial NN, Korsmeyer SJ, et al. Cell death: Critical control points. Cell, 2004, 116(2): 205-219
7 Chen-yang JIANG, Chun GUI, Ai-na HE, et al. Optimal time for mesenchymal stem cell transplantation in rats with myocardial infarction. J Zhejiang Univ Sci B. 2008, 9(8): 630-637
8 Nor JE, Christensen J, Mooney DJ, et al. Vascular endothelial growth factor-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Pathol 1999, 154: 375-384
9 Shimin Dong, Yunhui Cheng, Jian Yang,et al. MicroRNA Expression Signature and the Role of MicroRNA-21 in the Early Phase of Acute Myocardial Infarction. Biol Chem, 2009, 284(43): 29514-29525
10 Cyrus J. Parsa, Jihee Kim, Ryan U. Riel, et al. Cardioprotective Effects of Erythropoietin in the Reperfused Ischemic Heart. THE JOURNAL OF BIOLOGICAL CHEMISTRY. 2004, 279: 20655-20662
11 Cagli k,Bagci C, Gulec M,et al.In vivo effects of caffeic acid phenethylester on myocardial ischemia-reperfusion injury and apoptotic changes in rats. Ann Clin Lab Sci, 2005,35(4):440-448
12 Emily H.-Y. A. Cheng, Michael C. Wei, Solly Weiler, et al. BCL-2, BCL-XL Sequester BH3 Domain-Only Molecules Preventing BAX- and BAK-Mediated Mitochondrial Apoptosis. Molecular Cell, 2001, 8, 705-711
13 Formigli L, Ibba-Manneschi L, Perna AM, et al. Ischemia-reperfusion-induced apoptosis and p53 expression in the course of rat heterotopic heart transplantation. Microvasc Res. 1998, 56(3): 277-281
14叶亮,杜心灵,夏家红等。重组人红细胞生成素对心肌梗死治疗作用的实验研究。中华医学杂志。2006,86:2776-2780
15 Tramontano AF, Muniyappa R, Black AD, et al. Erythropoietin protects cardiacmyocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun, 2003, 308(4): 990-994
16 Cai Z, Manalo DJ, wei G, et al. Hearts from rodents exposed to inter mittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation, 2003, 108(1): 79-85
17 Jun Yang, YuanGui Huang, Xin Yu, et al. Erythropoietin preconditioning supresses neuronal death following status epilepticus in rats. Acta Neurobiol Exp, 2007, 67: 141-148
18 Van der Meer P, Lipsic E, Henning RH, et al. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury. Eur J Heart Fail, 2004, 6(7): 853-859
19 Vincenti V, Cassano C, Rocchi M, et al. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation, 1996, 93(8): 1493-1495
20 Zachary I, Mathur A, Yla-Herttuala S, et al. Vascular protection: A novel nonangiogenic cardiovasular role for vascular endothelial growth factor. Arterioscler Thromb Vasc Biol, 2000, 20(6): 1512-1520
21 Servos S, Zachary I, Martin JF, et al. VEGF modulates NO production: the basis of a cytoprotective effect?. Cardiovasc Res, 1999, 41(3): 509-510
22 Ware JA, simons M, et al. Angiogenesis in ischemic heart disease. Nature Med, 1997, 3(2): 158-164
23 JW Yockman, D Choi, MG Whitten, et al. Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct. Gene Therapy, 2009, 16, 127-135
24 Yau TM, Kim C, Li G, et al. Maximizing ventricular function with multimodal cell-based fene therapy. Circulation, 2005, 112:I123-I128
25 Yoon YS, Uchida S, Masuo O. Progressive attenuation of myocardial vasular endothelial growth factor expression is a seminal event in diabetic cardiomypathy: Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation, 2005, 111: 2073-2085
26 Ruixing Y, Jiaquan L, Jie C, et al. Intravenous administration of vascular endothelial growth factor improves cardiac performance and inhibits cardiomyocyte apoptosis. Growth Factors, 2006, 24(3): 209-217
27 Ruixing Y, Dezhai Y, Hai W, et al. Intramyocardial injection of vascular endothelial growth factor gene improves cardiac performance and inhibits cardiomyocyte apoptosis. Eur J Heart Fail, 2007, 9(4): 343-351
28 Hiroaki Sasaki, Shoji Fukuda, Hajime Otani, et al. Hypoxic Preconditioning Triggers Myocardial Angiogenesis: a Novel Approach to Enhance Contractile Functional Reserve in Rat with Myocardial Infarction. Mol Cell Cardiol, 2002,34, 335-348
29 Gerber HP, Mcmurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates cell survival through the phosphatidylinositol 3′-Kinase/Akt signal transduction pathway. Biol Chem, 1998, 273: 46: 30336-30343
30 Uemura R, Xu M, Ahmad N, et al. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res, 2006, 98: 1414-1421
31 Xu M, Uemura R, Dai Y, et al. In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. Mol Cell Cardiol, 2007, 42: 441- 448
1 Elmore S, et al. Apoptosis: a review of programmed cell death. Toxicol pathol, 2007, 35(4):495-516
2 Piper HM, Meuter K, Schafer C, et al. Cellular mechanismss of ischemia-reperfusion injury. Ann Thorac Surg, 2003, 75(2): S644-648
3谢俊然,郁丽娜,段世明.心肌缺血再灌注损伤心肌细胞凋亡的分子调节机制。国外医学麻醉学与复苏分册,2005,26(4):226-228
4 Yellon DM, Hausenloy DJ, et al. Myocardial reperfusion injury. N Engl J Med. 2007; 357(11): 1121-1135
5孙涛,苏全生。自由基与心肌缺血/再灌注损伤。实用医院临床杂志,2006,3 (4):94-96
6 Zhang C, Xu X, Potter B J, et al. TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol, 2006, 26 (3): 475-480
7 Kim JK, Pedram A, RazandiM, et al. Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms. J Biol Chem, 2006, 281 (10) : 6760-6767
8 Petrosillo G, Ruggiero FM, Divenosa N, et al. Decreased complexIII activity in mitochondria isolated from rat heart subjected to ischemia and reperfusion: role of reactive oxygen species and cardiolipin. FAS EB J , 2003, 17 (6): 714-716
9 Nordlie MA, Wold LE, Simkhovich BZ, et al. Molecular aspects of ischemic heart disease: ischemia/reperfusion-induced genetic changes and potential applications of gene and RNA interference therapy. J Cardiovasc Pharmacol Ther, 2006, 11 (1): 17-30
10 Vempati UD, Diaz F, Barrientos A, et al. Role of cytochrome C in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but notwith lack of cytochrome C release. Mol Cell Biol, 2007, 27(5): 1771-1783
11 Belizario JE, Alves J, Occhiucci JM, et al. A mechanistic view of mitochondrial death decision pores. Braz J Med Biol Res, 2007, 40(8): 1011-1024
12 Wang J, Zhang Z, Hu Y, et al. SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse vetricular myocytes. Physiol Res, 2007, 56(1): 17-23
13 Agocha A, Lee HW, et al. Hhpoxia regulates basal and induced DNA synthesis and collagen typeⅠproduction in human cardiac fibrobrasts: effects of transforming growth factor-β1, thyroid hormone, angiotensin II and basic fibrobrasts growth factor. J Mol Cell Cardiol, 1997, 29 (8): 2233-2244
14 Haudek SB, Taffet GE, Schneider MD, et al. TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways. J Clin Invest, 2007, 117 (9): 2692-2701
15 Dhingra S, Sharma A K, Singla D K, et al. P38 and ERK1/2 MAPKs mediate the interplay of TNF-alpha and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis. Am J Physiol Heart Circ Physiol, 2007, 293 (6) : 3524-3531
16 Braithwaite AW, Prives CL, et al. P53: more research and more questions. Cell Death Differ 2006, 13(6): 877-880
17 Alvarez S, Drane P, Meiller A, et al. A comprehensive study of p53 transcriptional activity in thymus and spleen of gamma irradiated mouse: High sensitivity of genes involved in the two main apoptotic pathways. Int J Radiat Biol 2006; 82(11): 761-770
18 Wang DS, Li Y, Dou KF, et al. Utility of adenovirus-mediated Fas ligand and bcl-2 gene transfer to modulate rat liver allograft survival. Hepatobiliary Pancreat Dis Int, 2006, 5(4): 505-510
19 Du C, Wang S, Diao H, et al. Increasing resistance of tubular epithelial cells to apoptosis by shRNA therapy ameliorates renal ischemia-reperfusion injury. Am J Transplant, 2006, 6 (10): 2256-2267
20 Davidson SM, Hausenloy D, Duchen MR, et al. Signalling via thereperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem cell Biol. 2006, 38 (3): 414-419
21 Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, et al. Stimulation of the stress activated mitogen-activated protein kinase subfamilies in perfused heart, p38/RK mitogen- activated protein kinasesand c-Jun N- terminal kinases are activated by ischemia/reperfusion. Circ Res, 1996, 79: 162-173
22 MOOSAVIM A, YAZDANPARAST R, LOTFI A, et al. ERK1/2 inactivation and p38 MAPK-dependent caspase activation during guanosine 5’-triphosphate-mediated terminal erythroid differentiation of K562 cells. Int J Biochem Cell Biol, 2007, 39(9): 1685-1697
23 Li Z, Ma JY, Kerr I, et al. Selective inhibition of p38α-MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. Am J Physiol Heart Circ Physiol, 2006, 291(4): H1 972-H1977
24 Negoro S, Kunisada K, Tone E, et a1. Activation of JAK/STAT pathway transduces cytop rotective signal in rat acute myocardial infarction. Cardiovasc Res, 2000, 47 (4) : 797-805
25 Li D, Williams V, Liu L, et al. Expression of lectin-like oxidized low density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. J Am Coll Cardiol, 2003, 41 (6): 1048-1055
26 Hayashida K, Kume N, Murase T, et al. Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are elevated in acute coronary syndrome: a novel marker for early diagnosis. Circulation 2005, 112(6): 812- 818
27 Kadota J, Mizunoe S, Mukae H, et al. The expression of pro-and anti-apoptotic Bcl-2 family proteins in peribronchiolar lymphocytes from patients with diffuse panbronchiolitis. Respiratory Medicine, 2006, 100 (11): 2029-2036
28 Yildirim E, Ozisik K, Ozisik P, et al. Apoptosis-related gene Bcl-2 in lung tissue after experimental traumatic brain injury in rats. Heart, Lung & Circulation, 2006, 15 (2): 124-129
29 Hajnoczky G, Csordas G, Das S, et al. Mitochondrial calcium signalling and cell death: approaches for as sessing the role of mitochondrial Ca2+ uptake in apoptosis. Cell Calcium, 2006; 40(5-6): 553-560
30 Lu G, Kang YJ, Han J, et al. TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling. J Biol Chem, 2006, 281 (9): 6087 - 6095
31 Zhang H, et al. P53 plays a central role in UVA and UVB induced cell damage and apoptosis in melanoma cells. Cancer Lett, 2006, 244 (2): 229-238
32 Pelengaris S, Khan M, et al. The many faces of c-MYC. Arch Biochem Biophysics, 2003, 416 (2): 129-136
33 Zhuang WJ, Fong CC, Cao J, et al. Involvement of NF-κB and c-myc signaling pathways in the apoptosis of HL-60 cells induced by alkaloids of Tripterygium hypoglaucum (levl.)Hutch. Phytomedicine, 2004, 11 (4): 295-302
34 Nelson DP, Wechsler SB, Miura T, et al. Myocardial immediate early gene activation after cardiopulmonary bypass with cardiac ischemia reperfusion. Ann Thorac Surg, 2002, 73 (1): 156-162
35 Yang J, Marden JJ, Fan C, et al. Genetic redox preconditioning differentially modulates AP-1 and NF-kappa B responses following cardiac ischemia/reperfusion injury and protects against necrosis and apoptosis. Mol Ther, 2003, 7 (3) : 341-353
36 Kobara M, Tatsumi T, et al. Effects of ACE inhibition on myocardial apoptosis in an ischemia-reperfusion rat heart model. J Cardiovasc Pharmacol, 2003, 41 (6): 880-889
37 Parlakp inarH, Sahna E, et al. Protective effect of caffeic acid phenethyl ester (CAPE) on myocardial ischemia-reperfusion-induced apoptotic cell death. Toxicology, 2005, 209 (1): 1-14
38 Fu J, Lin G, Wu Z, et al. Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury. Biochem Biophys Res Commun. 2006, 349(2): 504-512
39 Liu HR, Gao F, et al. Antiapoptotic mechanismss of benidipine in the ischemic/reperfused heart. Br J Pharmacol, 2004, 142 (4) : 627-634
40 Satwani S , Dec GW, Narula J, et al. Beta-adrenergic blockers in heart failure: review of mechanismss of action and clinical outcomes. J Cardiovasc Pharmacol Ther, 2004; 9: 243-255