牡荆素对心肌缺血/再灌注损伤的保护作用及其作用机制
|
摘要
山楂系蔷薇科植物,是我国传统中药,有助消化作用。现代药理学研究发现,山楂叶中提取的黄酮类化合物具有降血脂、降血压、增加冠脉流量、保护心肌缺血、抗氧化等作用。牡荆素(vitexin,VT)是从山楂叶中提取的有效单体成分,其分子式为C_(21)H_(20)O_(10),分子量为432.4,毒性极低,但迄今为止,尚无对牡荆素的系统研究。因此,为加快开发利用牡荆素,本课题从以下几个方面对牡荆素进行研究,以探讨其防治心肌缺血/再灌注损伤的保护作用及其作用机制。
第一部分牡荆素对实验性急性心肌缺血的保护作用
1.牡荆素对气管夹闭小鼠心电持续时间的影响
采用夹闭气管致小鼠心肌缺氧的模型,观察小鼠尾静脉注射(iv)不同剂量牡荆素对其心电消失时间的影响。结果发现牡荆素12,6,3 mg·kg~(-1)3个剂量组小鼠心电消失的时间均显著长于NS对照组,最多可延长约32.94%,差异具有高显著性(P＜0.01)。提示牡荆素可显著提高小鼠心脏耐缺氧的能力。
2.牡荆素对异丙肾上腺素(Isoproterenol,Iso)诱发大鼠急性心肌缺血性损伤的保护作用
皮下注射(sc)Iso可导致大鼠出现急性心肌缺血,并产生典型的缺血心电图(electrocardiogram,ECG)改变。结果发现,模型组大鼠ECG S-T段在sc Iso后1min即开始明显抬高,5min时抬高更为显著,并一直持续至20min。牡荆素6,3,1.5mg·kg~(-1) 3个剂量组均可明显延S-T段异常抬高开始出现的时间,并可显著降低S-T段异常抬高的严重程度。另外,与对照组相比,模型组大鼠心肌含水量(MWC)增加1.89%,牡荆素6,3 mg·kg~(-1)剂量组可显著抑制大鼠心肌含水量(MWC)的增高,抑制缺血心肌组织水肿,对增加部分的抑制率分别达52.78%和38.19%(P＜0.01或P＜0.05)。
3.牡荆素对垂体后叶素(Pit)诱发大鼠心肌缺血性损伤的保护作用
在舌下静脉注射(iv)Pit诱发大鼠心肌损伤模型上,结果显示:注射Pit后,模型组大鼠各时间点ECG S-T段变化值与正常对照组比较,有显著性差异(P＜0.01);葛根素组与牡荆素(6,3 mg·kg~(-1))能显著降低Pit致大鼠心肌缺血升高的S-T段(P＜0.05或P＜0.01)。牡荆素(6,3 mg·kg~(-1))降低血清中乳酸脱氢酶(LDH)和肌酸磷酸激酶(CPK)的活力(P＜0.05或P＜0.01),同时升高血清中SOD及GSH-PX的活力(P＜0.05或P＜0.01),提示牡荆素可通过增强抗氧化能力对缺血心肌产生保护作用。牡荆素6,3,1.5 mg·kg~(-1)3个剂量组和葛根素组能明显升高缺血心肌组织中Na~+-K~+—ATPase,Ca~(2+)-Mg~(2+)-ATPase及总ATPase的活性(P＜0.05或P＜0.01),提示牡荆素可以改善缺血心肌的能量代谢,保护受损心肌细胞。牡荆素(6,3 mg·kg~(-1))可明显改善缺血心肌的病理损伤程度。
4.牡荆素对冠脉结扎(LAD)致大鼠急性心肌缺血的保护作用
将大鼠分为6组,麻醉开胸后结扎冠状动脉左前降支(LAD)复制急性心肌梗死(AMI)模型。手术后各组行不同处理,假手术组(仅穿线不结扎)和模型组iV等容积生理盐水,阳性药组iv 30 mg·kg~(-1)葛根素注射液,受试药小、中、大剂量组分别iv1.5,3.0,6.0 mg·kg~(-1)牡荆素。结果显示:牡荆素6,3,1.5 mg·kg~(-1)3个剂量组均可不同程度减小心肌的梗死范围(与模型组比较,P＜0.05或P＜0.01):降低大鼠血清中LDH和CPK(与模型组比较,P＜0.05或P＜0.01)活性。
5.牡荆素对结扎冠脉(LAD)致犬实验性急性心肌梗死的保护作用
采用麻醉犬冠状动脉左前降支(LAD)两步结扎复制急性心肌梗死模型。将36只杂种犬随机分为6组,手术后各组行不同处理,阳性药组iv 15 mg·kg~(-1)葛根素注射液,受试药小、中、大剂量组分别iv1.0,2.0,4.0 mg·kg~(-1)牡荆素,假手术组(仪穿线不结扎)和模型组iv等容积生理盐水。通过心外膜电图标测Σ-ST和N-ST,心肌切片氯化硝基四氮哇蓝(NBT)染色计算心肌梗死范围,抽取静脉血测定血清乳酸脱氢酶(LDH)、肌酸磷酸激酶(CK),观察牡荆素对犬急性心肌梗死的治疗作用。结果显示:牡荆素均不同程度抑制心肌缺血范围,减少心肌梗死面积,降低缺血心肌心梗指数(与模型组比较,P＜0.05或P＜0.01),并可降低血清中LDH和CK的活性(与模型组比较,P＜0.05或P＜0.01),牡荆素4,2 mg·kg~(-1)剂量组可抑制Σ-ST和N-ST升高程度。结果提示牡荆素对犬急性心肌梗死有较好的治疗作用。
6.牡荆素减轻大鼠血栓的湿重,抑制大鼠动静脉血栓的形成
在大鼠动静脉血栓形成实验中,与NS对照组相比,牡荆素6,3 mg·kg~(-1)剂量组可明显降低血栓的干重(P＜0.05),对血栓湿重虽有降低趋势,但差异尚无统计学意义。
第二部分牡荆素对离体大鼠心肌缺血/再灌注损伤的保护作用及机制
在离体大鼠Langendorff心肌缺血/再灌注模型上,研究了牡荆素对离体大鼠心肌缺血再灌注损伤(MIIR)的保护作用及其机制。我们观察了牡荆素对离体大鼠冠脉流量的影响,采用苏木素一伊红(HE)染色观察心肌组织病理改变,电镜法观察心肌组织超微结构的改变;检测心肌组织中乳酸脱氢酶(LDH)与肌酸磷酸肌酶(CPK)的活性,放免法检测心肌组织中肿瘤坏死因子-α(TNF-α)、白介素-1(IL-1β)的含量,免疫组织化学检测Bax,Bcl-2、细胞黏附分子-1(ICAM-1),NF-κBp65蛋白表达。实验结果显示:牡荆素可明显抑制离体大鼠冠脉流量的降低,并能不同程度地改善MI/R大鼠心肌病理及超微结构的改变,减少心肌组织中LDH,CPK,TNF-α,IL-1β释放,抑制心肌细胞凋亡、下调Bax基因、上调Bcl-2基因,抑制NF-κB p65蛋白表达。实验结果提示牡荆素对离体大鼠MI/R有保护作用,其机制与稳定心肌细胞膜结构,抑制炎症因子释放,通过下调Bax基因、上调Bcl-2基因抑制细胞凋亡,抑制NF-κB p65核移位等有关。
第三部分牡荆素预处理对缺氧复氧心肌细胞的保护作用及其作用机制
在培养的SD乳鼠心肌细胞缺氧/复氧(A/R)模型上,研究了牡荆素预处理后对A/R诱导心肌细胞损伤的保护作用及其作用机制。采用台盼蓝排斥实验检测心肌细胞存活率并收集细胞上清液,行LDH,CPK活性测定,以荧光素染料Hoechst33258测定心肌细胞凋亡率并用流式细胞法检测细胞凋亡,以Fluo-3/Am染色观察心肌细胞内[Ca~(2+)]_i的变化;制备心肌细胞蛋白提取物,以磷酸化的ERK1/2抗体测定ERK1/2活性,并观察ERKs的上游激酶(MEK1/2)抑制剂PD98059对于牡荆素预处理诱导的ERKs磷酸化以及对心肌保护作用的影响。结果显示:缺氧复氧可造成心肌细胞明显损伤,牡荆素预处理后可增加心肌细胞A/R后存活率,减少心肌细胞LDH和CPK的漏出,降低心肌细胞凋亡率,抑制心肌细胞内钙超载,并激活ERK1/2。提示牡荆素预处理可以提高乳鼠心肌细胞对于A/R的耐受性,对缺氧复氧心肌细胞具有保护作用,其机制涉及抗氧化、抑制细胞凋亡和钙超载以及激活ERK1/2有关。
结论:本文系统研究了牡荆素对心肌缺血及缺血再灌注损伤的保护作用,并对其抗心肌缺血作用机制进行了探索。研究发现牡荆素对心肌缺血及缺血再灌注损伤具有明显的保护作用,其作用机制涉及抗氧化、抑制炎症细胞因子释放和细胞凋亡,与抑制NF-κB p65核移位和细胞内钙超载以及激活ERK1/2也有关。
Crataegus pinnatifida Bunge(Botan-rosaceae) is a traditional Chinese medicine, which has digestive effect.It was found that the flavones,were extracted from Crataegus pinnatifida Bunge,could lower blood fat,have hypotensive effect,increase coronary flow and have protective effects on myocardial ischemic injury,etc.Vitexin,a flavone glycoside(8-C-β-D-glucopyranosyl-apigenin),is isolated from the leaf of Crataegus pinnatifida Bunge which is attributed with varied medicinal properties. Vitexin has been demonstrated to have hypotensive effect and anti-inflammatory action. However,there's been no study about vitexin on myocardial ischemic and reperfusion injury.This research therefore designed to observe the protective effect of vitexin on myocardial ischemic and reperfusion injury and the possible underlying mechanism.
PartⅠThe protective effects of vitexin on experimental myocardial ischemia model
1.Effect of vitexin on ECG time in trachea clamping mice
On the myocardial anoxia model induced by clamping trachea in mice,it is found that the ECG survival time was much longer in the groups pretreated with vitexin(12, 6,3 mg·kg~(-1)) than that in NS control group.The maximal elongation rate of ECG survival time reached a height of 32.94%.
2.Protective effect of vitexin on acute myocardial ischemia injury induced by isoproterenol in rats
Acute myocardial ischemia episodes and typical isehemia ECG developed after subcutaneous injection(sc) of Iso.The results showed that vitexin(6,3,1.5 mg·kg~(-1)) could ameliorate the changes of segment S-T of ECG(P＜0.05 or P＜0.01 compared with model).The myocardial water content(MWC) in model group was 1.89%higher than NS control.Vitexin(6,3 mg·kg~(-1)) can significantly inhibit the increase of MWC and the inhibition rates were 52.78%and 38.19%,respectively(P＜0.05 or P＜0.01 compared with model).
3.Protective effects of vitexin on experimental myocardial ischemia induced by pituitrin in rats
To explore the protective effects of vitexin on experimental acute myocardial ischemia induced by pituitrin(Pit) in rats.The ischemia model was established induced by 1.5 IU·kg~(-1) Pit through intravenous injection.It was showed that the S-T segment of ECG in model group rosed significantly at 30 second,1min,5min,10min,20min of ischemia induced by Pit(P＜0.01 compared with control).The administration of vitexin (6,3,1.5 mg·kg~(-1)) markedly decreased the elevation of segment S-T of ECG(P＜0.05 or P＜0.01 compared with model),reduced the activity of lactate dehydrogenase(LDH) and creatine phosphokinase(CPK) and increased the activity of superoxide dismutase (SOD) and glutathione peroxidase(GSH-PX) in the serum of rats(P＜0.05 or P＜0.01 compared with model),vitexin(6,3,1.5 mg·kg~(-1)) significantly increased the activity of ATPase in the myocardium of rats(P＜0.05 or P＜0.01 compared with model).The administration of vitexin(6,3 mg·kg~(-1)) improved myocardial pathologic alternation.
4.Protective effects of vitexin on experimental myocardial infarction by ligating left anterior descending coronary artery in rats
To study the protective effect of vitexin on experimental acute myocardial infarction(AMI) by ligating left anterior descending coronary artery(LAD) in rats.The results showed that vitexin(6,3,1.5 mg·kg~(-1)) could decrease the infarction range marked by N-BT staining,and vitexin(6,3mg·kg~(-1)) could reduce the activities of lactate dehydrogenase(LDH) and creatine phosphokinase(CPK) in the serum of rats(P＜0.05 or P＜0.01 compared with model).
5.Protective effects of vitexin on experimental myocardial infarction by ligating left anterior descending coronary artery in dogs
To observe the protective effect of vitexin on experimental acute myocardial infarction(AMI) by ligating left anterior descending coronary artery(LAD) in dogs.36 hybrid dogs were divided into 6groups at random.Vitexin(6,3,1.5 mg·kg~(-1)) could decrease the myocardial ischemic risk and the infarction size,and vitexin(6,3 mg·kg~(-1)) could decrease the myocardial index(MI)(P＜0.05 or P＜0.01 compared with model) in dogs as well.it was seen that vitexin could reduce the degree of myocardial infarction (Σ-ST) and the myocardial infarction range(N-ST) in dogs(P＜0.05 or P＜0.01 compared with model).At the same time,vitexin could reduce the activities of lactate dehydrogenase(LDH) and ereatine phosphokinase(CPK) in the serum of dogs(P＜0.05 or P＜0.01 compared with model).
6.Effect of vitexin on the formation of throbosis on the A-V thrombosis pass-by model in rats
To observe the effect of vitexin on the formation of throbosis on the A-V thrombosis pass-by model in rats.The results showed that vitexin(6,3 mg·kg~(-1)) could obviously decrease the dry weight of thrombosis on the A-V thrombosis pass-by model.
PartⅡThe effects and mechanism of vitexin on myocardial ischemia/reperfusion injury in rats in vitro
To study the effect and mechanism of vitexin on myocardium ischemia/reperfusion in rats in vitro.To set rats model of MI/R in vitro,and observe the coronary flow and pathologic changes of myocardium with HE staining,give a morphological observation with TEM,and detect tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β) with RIA, apoptosis rate of myocardium with TUNEL,protein expression of Bax,Bcl-2,ICAM-1 and NF-κB p65 with immunohistochemical method.The results showed that vitexin could significantly inhibit the reductions of coronary flow,and improve myocardial pathologic and ultrastructure changes in MI/R,reduce the contents of TNF-α、IL-1βin myocardial homogenate,inhibit apoptosis of cardiac muscle cell,down regulate the expression of Bax gene and up regulate the expression of Bcl-2 gene,and inhibit the protein expression of NF-κB p65.
PartⅢMechanisms of vitexin preconditioning effects on cultured neonatal rat cardiomyocytes with anoxia and reoxygenation
To observe the protective effects and its mechanism of vitexin preconditioning (VPC) on cultured neonatal rat cardiomyocytes after anoxia and reoxygenation(A/R). An A/R model was established using cultured neonatal rat cardiomyocytes.Cellular injury was evaluated by measuring cell viability,the releases of creatine kinase(CPK), and lactate dehydrogenase(LDH).We measured the apoptosis rate of cardiomyocytes after Anoxia/reoxygenation,activities of extracellular signal-regulated protein kinases (ERKs).The intracellular calcium indicated by the fluorescence in cardiomyocytes was measured by the laser confocal microscope.The results showed that 10,30 and 100μmol/L Vitexin preconditioning significantly enhanced the cell viability from 82.47±0.97(A/R group) to 91.58±1.32%,93.44±0.89%and 95.87±0.73%(p＜0.01), respectively.Vitexin preconditioning(10,30 and 100μmol/L) markedly inhibited A/R-induced increases of LDH and CPK release(p＜0.05 or p＜0.01).By using Hoechst33258 method,it was found that vitexin preconditioning 10,30,100μmol/L obviously decreased the number of apoptotic cardiomyocytes(p＜0.01).The examination of flow cytometer(FCM) method also showed in range of 10～100μmol/L, vitexin preconditioning had significant inhibitory effect on A/R-induced cardiomyocytes apoptosis.Vitexin preconditioning 10,30 and 100μmol/L markedly decreased the fluorescence intensity value of[Ca~(2+)]_i in cardiomyocytes from 37.78±4.90(A/R group) to 28.65±6.12,26.55±4.53 and 23.15±3.85((p＜0.05 or p＜0.01),respectively.The band for phospho-ERK was observed in cardiomyocytes of each group.Exposure to anoxia or vitexin preconditioning significantly increased the phospho-ERK level,and the increase was markedly inhibited by PD98059,an inhibitor of the upstream kinase of ERK.
Conclusions:The protective effects and mechanism in anti-myocardial ischemia and reperfusion of vitexin were studied.It was found that vitexin could protect heart against myocardial ischemia and reperfusion injury,the protective mechanism may related with anti-oxidation,inhibiting inflammatory factor releasing and the cardiomyocytes apoptosis,lowing the cardiomyocytes calcium overload and inhibiting nuclear ectopy of NF-κB p65 and increasing the abundance of phosphor-ERK1/2 of the cardiomyocytes.
第一部分牡荆素对实验性急性心肌缺血的保护作用
1.牡荆素对气管夹闭小鼠心电持续时间的影响
采用夹闭气管致小鼠心肌缺氧的模型,观察小鼠尾静脉注射(iv)不同剂量牡荆素对其心电消失时间的影响。结果发现牡荆素12,6,3 mg·kg~(-1)3个剂量组小鼠心电消失的时间均显著长于NS对照组,最多可延长约32.94%,差异具有高显著性(P＜0.01)。提示牡荆素可显著提高小鼠心脏耐缺氧的能力。
2.牡荆素对异丙肾上腺素(Isoproterenol,Iso)诱发大鼠急性心肌缺血性损伤的保护作用
皮下注射(sc)Iso可导致大鼠出现急性心肌缺血,并产生典型的缺血心电图(electrocardiogram,ECG)改变。结果发现,模型组大鼠ECG S-T段在sc Iso后1min即开始明显抬高,5min时抬高更为显著,并一直持续至20min。牡荆素6,3,1.5mg·kg~(-1) 3个剂量组均可明显延S-T段异常抬高开始出现的时间,并可显著降低S-T段异常抬高的严重程度。另外,与对照组相比,模型组大鼠心肌含水量(MWC)增加1.89%,牡荆素6,3 mg·kg~(-1)剂量组可显著抑制大鼠心肌含水量(MWC)的增高,抑制缺血心肌组织水肿,对增加部分的抑制率分别达52.78%和38.19%(P＜0.01或P＜0.05)。
3.牡荆素对垂体后叶素(Pit)诱发大鼠心肌缺血性损伤的保护作用
在舌下静脉注射(iv)Pit诱发大鼠心肌损伤模型上,结果显示:注射Pit后,模型组大鼠各时间点ECG S-T段变化值与正常对照组比较,有显著性差异(P＜0.01);葛根素组与牡荆素(6,3 mg·kg~(-1))能显著降低Pit致大鼠心肌缺血升高的S-T段(P＜0.05或P＜0.01)。牡荆素(6,3 mg·kg~(-1))降低血清中乳酸脱氢酶(LDH)和肌酸磷酸激酶(CPK)的活力(P＜0.05或P＜0.01),同时升高血清中SOD及GSH-PX的活力(P＜0.05或P＜0.01),提示牡荆素可通过增强抗氧化能力对缺血心肌产生保护作用。牡荆素6,3,1.5 mg·kg~(-1)3个剂量组和葛根素组能明显升高缺血心肌组织中Na~+-K~+—ATPase,Ca~(2+)-Mg~(2+)-ATPase及总ATPase的活性(P＜0.05或P＜0.01),提示牡荆素可以改善缺血心肌的能量代谢,保护受损心肌细胞。牡荆素(6,3 mg·kg~(-1))可明显改善缺血心肌的病理损伤程度。
4.牡荆素对冠脉结扎(LAD)致大鼠急性心肌缺血的保护作用
将大鼠分为6组,麻醉开胸后结扎冠状动脉左前降支(LAD)复制急性心肌梗死(AMI)模型。手术后各组行不同处理,假手术组(仅穿线不结扎)和模型组iV等容积生理盐水,阳性药组iv 30 mg·kg~(-1)葛根素注射液,受试药小、中、大剂量组分别iv1.5,3.0,6.0 mg·kg~(-1)牡荆素。结果显示:牡荆素6,3,1.5 mg·kg~(-1)3个剂量组均可不同程度减小心肌的梗死范围(与模型组比较,P＜0.05或P＜0.01):降低大鼠血清中LDH和CPK(与模型组比较,P＜0.05或P＜0.01)活性。
5.牡荆素对结扎冠脉(LAD)致犬实验性急性心肌梗死的保护作用
采用麻醉犬冠状动脉左前降支(LAD)两步结扎复制急性心肌梗死模型。将36只杂种犬随机分为6组,手术后各组行不同处理,阳性药组iv 15 mg·kg~(-1)葛根素注射液,受试药小、中、大剂量组分别iv1.0,2.0,4.0 mg·kg~(-1)牡荆素,假手术组(仪穿线不结扎)和模型组iv等容积生理盐水。通过心外膜电图标测Σ-ST和N-ST,心肌切片氯化硝基四氮哇蓝(NBT)染色计算心肌梗死范围,抽取静脉血测定血清乳酸脱氢酶(LDH)、肌酸磷酸激酶(CK),观察牡荆素对犬急性心肌梗死的治疗作用。结果显示:牡荆素均不同程度抑制心肌缺血范围,减少心肌梗死面积,降低缺血心肌心梗指数(与模型组比较,P＜0.05或P＜0.01),并可降低血清中LDH和CK的活性(与模型组比较,P＜0.05或P＜0.01),牡荆素4,2 mg·kg~(-1)剂量组可抑制Σ-ST和N-ST升高程度。结果提示牡荆素对犬急性心肌梗死有较好的治疗作用。
6.牡荆素减轻大鼠血栓的湿重,抑制大鼠动静脉血栓的形成
在大鼠动静脉血栓形成实验中,与NS对照组相比,牡荆素6,3 mg·kg~(-1)剂量组可明显降低血栓的干重(P＜0.05),对血栓湿重虽有降低趋势,但差异尚无统计学意义。
第二部分牡荆素对离体大鼠心肌缺血/再灌注损伤的保护作用及机制
在离体大鼠Langendorff心肌缺血/再灌注模型上,研究了牡荆素对离体大鼠心肌缺血再灌注损伤(MIIR)的保护作用及其机制。我们观察了牡荆素对离体大鼠冠脉流量的影响,采用苏木素一伊红(HE)染色观察心肌组织病理改变,电镜法观察心肌组织超微结构的改变;检测心肌组织中乳酸脱氢酶(LDH)与肌酸磷酸肌酶(CPK)的活性,放免法检测心肌组织中肿瘤坏死因子-α(TNF-α)、白介素-1(IL-1β)的含量,免疫组织化学检测Bax,Bcl-2、细胞黏附分子-1(ICAM-1),NF-κBp65蛋白表达。实验结果显示:牡荆素可明显抑制离体大鼠冠脉流量的降低,并能不同程度地改善MI/R大鼠心肌病理及超微结构的改变,减少心肌组织中LDH,CPK,TNF-α,IL-1β释放,抑制心肌细胞凋亡、下调Bax基因、上调Bcl-2基因,抑制NF-κB p65蛋白表达。实验结果提示牡荆素对离体大鼠MI/R有保护作用,其机制与稳定心肌细胞膜结构,抑制炎症因子释放,通过下调Bax基因、上调Bcl-2基因抑制细胞凋亡,抑制NF-κB p65核移位等有关。
第三部分牡荆素预处理对缺氧复氧心肌细胞的保护作用及其作用机制
在培养的SD乳鼠心肌细胞缺氧/复氧(A/R)模型上,研究了牡荆素预处理后对A/R诱导心肌细胞损伤的保护作用及其作用机制。采用台盼蓝排斥实验检测心肌细胞存活率并收集细胞上清液,行LDH,CPK活性测定,以荧光素染料Hoechst33258测定心肌细胞凋亡率并用流式细胞法检测细胞凋亡,以Fluo-3/Am染色观察心肌细胞内[Ca~(2+)]_i的变化;制备心肌细胞蛋白提取物,以磷酸化的ERK1/2抗体测定ERK1/2活性,并观察ERKs的上游激酶(MEK1/2)抑制剂PD98059对于牡荆素预处理诱导的ERKs磷酸化以及对心肌保护作用的影响。结果显示:缺氧复氧可造成心肌细胞明显损伤,牡荆素预处理后可增加心肌细胞A/R后存活率,减少心肌细胞LDH和CPK的漏出,降低心肌细胞凋亡率,抑制心肌细胞内钙超载,并激活ERK1/2。提示牡荆素预处理可以提高乳鼠心肌细胞对于A/R的耐受性,对缺氧复氧心肌细胞具有保护作用,其机制涉及抗氧化、抑制细胞凋亡和钙超载以及激活ERK1/2有关。
结论:本文系统研究了牡荆素对心肌缺血及缺血再灌注损伤的保护作用,并对其抗心肌缺血作用机制进行了探索。研究发现牡荆素对心肌缺血及缺血再灌注损伤具有明显的保护作用,其作用机制涉及抗氧化、抑制炎症细胞因子释放和细胞凋亡,与抑制NF-κB p65核移位和细胞内钙超载以及激活ERK1/2也有关。
Crataegus pinnatifida Bunge(Botan-rosaceae) is a traditional Chinese medicine, which has digestive effect.It was found that the flavones,were extracted from Crataegus pinnatifida Bunge,could lower blood fat,have hypotensive effect,increase coronary flow and have protective effects on myocardial ischemic injury,etc.Vitexin,a flavone glycoside(8-C-β-D-glucopyranosyl-apigenin),is isolated from the leaf of Crataegus pinnatifida Bunge which is attributed with varied medicinal properties. Vitexin has been demonstrated to have hypotensive effect and anti-inflammatory action. However,there's been no study about vitexin on myocardial ischemic and reperfusion injury.This research therefore designed to observe the protective effect of vitexin on myocardial ischemic and reperfusion injury and the possible underlying mechanism.
PartⅠThe protective effects of vitexin on experimental myocardial ischemia model
1.Effect of vitexin on ECG time in trachea clamping mice
On the myocardial anoxia model induced by clamping trachea in mice,it is found that the ECG survival time was much longer in the groups pretreated with vitexin(12, 6,3 mg·kg~(-1)) than that in NS control group.The maximal elongation rate of ECG survival time reached a height of 32.94%.
2.Protective effect of vitexin on acute myocardial ischemia injury induced by isoproterenol in rats
Acute myocardial ischemia episodes and typical isehemia ECG developed after subcutaneous injection(sc) of Iso.The results showed that vitexin(6,3,1.5 mg·kg~(-1)) could ameliorate the changes of segment S-T of ECG(P＜0.05 or P＜0.01 compared with model).The myocardial water content(MWC) in model group was 1.89%higher than NS control.Vitexin(6,3 mg·kg~(-1)) can significantly inhibit the increase of MWC and the inhibition rates were 52.78%and 38.19%,respectively(P＜0.05 or P＜0.01 compared with model).
3.Protective effects of vitexin on experimental myocardial ischemia induced by pituitrin in rats
To explore the protective effects of vitexin on experimental acute myocardial ischemia induced by pituitrin(Pit) in rats.The ischemia model was established induced by 1.5 IU·kg~(-1) Pit through intravenous injection.It was showed that the S-T segment of ECG in model group rosed significantly at 30 second,1min,5min,10min,20min of ischemia induced by Pit(P＜0.01 compared with control).The administration of vitexin (6,3,1.5 mg·kg~(-1)) markedly decreased the elevation of segment S-T of ECG(P＜0.05 or P＜0.01 compared with model),reduced the activity of lactate dehydrogenase(LDH) and creatine phosphokinase(CPK) and increased the activity of superoxide dismutase (SOD) and glutathione peroxidase(GSH-PX) in the serum of rats(P＜0.05 or P＜0.01 compared with model),vitexin(6,3,1.5 mg·kg~(-1)) significantly increased the activity of ATPase in the myocardium of rats(P＜0.05 or P＜0.01 compared with model).The administration of vitexin(6,3 mg·kg~(-1)) improved myocardial pathologic alternation.
4.Protective effects of vitexin on experimental myocardial infarction by ligating left anterior descending coronary artery in rats
To study the protective effect of vitexin on experimental acute myocardial infarction(AMI) by ligating left anterior descending coronary artery(LAD) in rats.The results showed that vitexin(6,3,1.5 mg·kg~(-1)) could decrease the infarction range marked by N-BT staining,and vitexin(6,3mg·kg~(-1)) could reduce the activities of lactate dehydrogenase(LDH) and creatine phosphokinase(CPK) in the serum of rats(P＜0.05 or P＜0.01 compared with model).
5.Protective effects of vitexin on experimental myocardial infarction by ligating left anterior descending coronary artery in dogs
To observe the protective effect of vitexin on experimental acute myocardial infarction(AMI) by ligating left anterior descending coronary artery(LAD) in dogs.36 hybrid dogs were divided into 6groups at random.Vitexin(6,3,1.5 mg·kg~(-1)) could decrease the myocardial ischemic risk and the infarction size,and vitexin(6,3 mg·kg~(-1)) could decrease the myocardial index(MI)(P＜0.05 or P＜0.01 compared with model) in dogs as well.it was seen that vitexin could reduce the degree of myocardial infarction (Σ-ST) and the myocardial infarction range(N-ST) in dogs(P＜0.05 or P＜0.01 compared with model).At the same time,vitexin could reduce the activities of lactate dehydrogenase(LDH) and ereatine phosphokinase(CPK) in the serum of dogs(P＜0.05 or P＜0.01 compared with model).
6.Effect of vitexin on the formation of throbosis on the A-V thrombosis pass-by model in rats
To observe the effect of vitexin on the formation of throbosis on the A-V thrombosis pass-by model in rats.The results showed that vitexin(6,3 mg·kg~(-1)) could obviously decrease the dry weight of thrombosis on the A-V thrombosis pass-by model.
PartⅡThe effects and mechanism of vitexin on myocardial ischemia/reperfusion injury in rats in vitro
To study the effect and mechanism of vitexin on myocardium ischemia/reperfusion in rats in vitro.To set rats model of MI/R in vitro,and observe the coronary flow and pathologic changes of myocardium with HE staining,give a morphological observation with TEM,and detect tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β) with RIA, apoptosis rate of myocardium with TUNEL,protein expression of Bax,Bcl-2,ICAM-1 and NF-κB p65 with immunohistochemical method.The results showed that vitexin could significantly inhibit the reductions of coronary flow,and improve myocardial pathologic and ultrastructure changes in MI/R,reduce the contents of TNF-α、IL-1βin myocardial homogenate,inhibit apoptosis of cardiac muscle cell,down regulate the expression of Bax gene and up regulate the expression of Bcl-2 gene,and inhibit the protein expression of NF-κB p65.
PartⅢMechanisms of vitexin preconditioning effects on cultured neonatal rat cardiomyocytes with anoxia and reoxygenation
To observe the protective effects and its mechanism of vitexin preconditioning (VPC) on cultured neonatal rat cardiomyocytes after anoxia and reoxygenation(A/R). An A/R model was established using cultured neonatal rat cardiomyocytes.Cellular injury was evaluated by measuring cell viability,the releases of creatine kinase(CPK), and lactate dehydrogenase(LDH).We measured the apoptosis rate of cardiomyocytes after Anoxia/reoxygenation,activities of extracellular signal-regulated protein kinases (ERKs).The intracellular calcium indicated by the fluorescence in cardiomyocytes was measured by the laser confocal microscope.The results showed that 10,30 and 100μmol/L Vitexin preconditioning significantly enhanced the cell viability from 82.47±0.97(A/R group) to 91.58±1.32%,93.44±0.89%and 95.87±0.73%(p＜0.01), respectively.Vitexin preconditioning(10,30 and 100μmol/L) markedly inhibited A/R-induced increases of LDH and CPK release(p＜0.05 or p＜0.01).By using Hoechst33258 method,it was found that vitexin preconditioning 10,30,100μmol/L obviously decreased the number of apoptotic cardiomyocytes(p＜0.01).The examination of flow cytometer(FCM) method also showed in range of 10～100μmol/L, vitexin preconditioning had significant inhibitory effect on A/R-induced cardiomyocytes apoptosis.Vitexin preconditioning 10,30 and 100μmol/L markedly decreased the fluorescence intensity value of[Ca~(2+)]_i in cardiomyocytes from 37.78±4.90(A/R group) to 28.65±6.12,26.55±4.53 and 23.15±3.85((p＜0.05 or p＜0.01),respectively.The band for phospho-ERK was observed in cardiomyocytes of each group.Exposure to anoxia or vitexin preconditioning significantly increased the phospho-ERK level,and the increase was markedly inhibited by PD98059,an inhibitor of the upstream kinase of ERK.
Conclusions:The protective effects and mechanism in anti-myocardial ischemia and reperfusion of vitexin were studied.It was found that vitexin could protect heart against myocardial ischemia and reperfusion injury,the protective mechanism may related with anti-oxidation,inhibiting inflammatory factor releasing and the cardiomyocytes apoptosis,lowing the cardiomyocytes calcium overload and inhibiting nuclear ectopy of NF-κB p65 and increasing the abundance of phosphor-ERK1/2 of the cardiomyocytes.
引文
[1].Raggi P.Coronary-calcium screening to improve risk stratification in primary prevention.J La State Med Soc,2002;154(6):314-318.
[2].Sekikawa,Horiuchi,Edmundowicz,et al.A "natural experiment" incardiovascular epidemiology in the early 21st century.Heart,2003;89:255-257.
[3].Maxwell SR,Lip GY.Reperfusion injury:a review of the pathophysiology,clinical manifestations and therapeutic options.Int J Cardiol,1997;58:95-117.
[4].Piper HM,et al.Afresh look at reperfusion injury.Cardiovas Res,1998;38:291-300.
[5].Bolli R.Basic and clinical aspects of myocardial stunning.Prog Cardiovas Dis,1998;40:477-516.
[6].PAJ Krijnen,R Nijmeijer,CJLM Meijer,et al.Apoptosis in myocardial ischaemia and infarction.J Clin Pathol,2002;55:801-811.
[7].Fliss H.Apoptosis in ischemic and reperfused rat myocardium.Circ Res,1996;79:949-956.
[8].Piot CA.Ischemic preconditioning decrease apoptosis in rat heart in vivo.Circulation,1997;96:1598-1604.
[9].Zhao ZQ,Nakamura M,Wang Nf,et al.Reperfusion induces myocardial apoptotic cell death.Cardiovasc Res,2000;45:651-660.
[10].Murry CE,Jennings RB,Reimer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium.Circulation 1986;74:1124-36.
[11].许正斌,高奎斌,许双贵.山楂叶综述[J].中医药学报,1985,4:49-50.
[12].斯建勇,陈迪华,高兴跃.云南山楂叶化学成分的研究[J].中国中药杂志,1998,23(7):422-424.
[13].叶希韵,王耀发.山楂叶总黄酮对血管内皮细胞氧化损伤的保护作用[J].中国现代应用药学杂志,2002,19(4):265-267.
[14].后德辉.一种简便的抗心肌缺氧药物筛选方法.蚌埠医学院学报,1998,23 (6):372-374
[15].王玉梅,刘兴君,王敏伟.赞丹松口服液对实验性心肌缺血的影响.中国民族医学杂志,2002,8(3):37-38
[16].朱玲,蔡绍辉,刘于宾,等.金泽冠心胶囊药效学实验研究.华西药学杂志,2000,15(6):428-429
[17].徐叔云,卞如濂,陈修主编.药理实验方法学(第三版),北京:人民卫生出版社,2002:1052-1054
[18].张英,李著华,王顺蓉,等.杏丁预处理对实验性兔急性心肌缺血的保护作用.中国煤炭工业医学杂志,2002,5(5):508-509
[19].Banai S,Jaklitsch MT,Shou M,et al.Angiogenic induced enhance mentofcol lateral blood flow to is chmicmy cardium by VEGF in dogs[J].Circulation,1994,25(9):530-532.
[20].陈铎葆,刘建国,管云风,等.红花黄素Ⅲ对犬缺血心肌的影响[J].中国药理学通报,2000,16(5):590-591.
[21]..徐叔云,卞如濂,陈修主编.药理实验方法学(第三版),北京:人民卫生出版社,2002:1054.
[22].于占久,王炳璋,杨鸣岗,等.关于心肌梗死的实验研究Ⅰ—动物模型的建立及心外膜电图标测术[J].中华心血管病杂志,1980,8(1):65-67.
[23].徐叔云,卞如濂,陈修主编.药理实验方法学(第三版),北京:人民卫生出版社,2002:1283-1284
[24].Rahimi AR,Marzano PM 3rd,Richard CM.Evaluation of lactate and C-reactive protein in the assessment of acute myocardial infarction[J].South Med J,2003;96(11):1107-1112.
[25].Juarez U,Trejo W,Whente M,et al.The usefulness of determining myoglobin,creatine ph0sphokinase MB isoenzyme,lactate dehydrogenase and aspartate aminotransferase in the diagnosis of acute myocardial infart[J].Arch Inst Cardiol Mex,1998;68(3):214-217.
[26].HaCPKenbroCPK CPK,Baue AE,Johnson D,et al.Lateral diffusion and electron tranfer in the mitochondrial inner membrane[J].Trends Biochem Sci,1998;6:151-158.
[27].Slater EC,Toda K,Kayano K,et al.A hypothesis for the mechanism of respiratory chain phosphorylation not involving the electrochemical gradient of protons as obligatory intermedicate[J].Biochem Biophys Acta,1995;8:211-217.
[28].叶萍仙,朱建华,夏强.脂质体携载前列腺素El抗心肌缺血再灌注损伤.中国药理学通报,2001;17(3):302-305.
[29].Lenen S,Gorlich JK,RustenbeCPK I,et al.Regulation of transmembrane in transport by reaction products of phospholipase as infects of lypiphospholipilid on mitochondrial Ca~(2+) transport[J].Biochem Biophys Acta,1999;982:140-146.
[30].Salvatore Cuzzocrea,Dennis P.Riley,Achille P.Caputi and Daniela Salvemini.Antioxidant Therapy:A New Pharmacological Approach In ShoCPK,Inflammation,and Ischemia/Reperfusion Injury.Pharmacological Reviews,2001,53(1):135-159.
[31].Dart RC,Sanders AB.Oxygen free radicals and myocardial reperfusion injury.,Ann Emerg Med,1988;17(1):53-58.
[32].Flitter WD.Free radicals and myocardial reperfusion injury.Br Med Bull 1993;49(3):545-555.
[33].McLeod LL,Sevanian A.Lipid peroxidation and modification of lipid composition in an endothelial cell model of ischemia and reperfusion.Free Radic Biol Med,1997;23(4):680-694.
[34].Hillis LD,Braunwald E.Myocardial ischemia.New Rngl Med,1977;296(18):1034-1041.
[35].范丽,郭岩,陈志武,等.黄蜀葵花总黄酮保护离体大鼠心肌缺血再灌注损伤的研究[J].中国药理学通报,2003,19(2):191-193.
[36].Holmberg SR,Cunmming DV,Kusarna Y,et al.Reactive oxygen species midify the structure and function of the cardiac sarcoplasmic reticulum calcium channel[J].Cardio Science,1991,2:19-25.
[37].Goldhaber JI,Ji S,Lamp ST,Weiss JN.Effects of exogenous free radicals onelectromechanical function and metabolism in isolated rabbit and guinea pig ventricle:implications for ischemia and reperfusion injury[J].J Clin Invest,1988,83(6):180-189.
[38].Scott Kinlay,Peter Ganz.Role of endothelial dysfunction in coronary artery disease and implications for therapy[J].Am J Cardiol,1997;80(9A):11I-6I.
[39].Nikolaos GF,Smith CW,Mark LE.The inflammatory response in myocardial infarction[J].Cardiovasc Res,2002,53(1):31-47.
[40].徐叔云,卞如濂,陈修等.药理学方法学(第三版),北京:人民卫生出版社,2002:987-989.
[41].Ozmen L,Aguet M.The in vivo antiviral activity of interleukin-12 is mediated by Gamma interferon.J Virology,1995,69:8147.
[42].Frangogiannis NG,Smith CW,Entman M.The inflammatory response in myocardial infarction.Cardiovasc Res,2002;53(1):31-47.
[43].Meldrum DR,Cleveland JC Jr,Cain BS,et al.Increased myocardial tumor necrosis factor alpha in a crystalloid perfused model of cardiac ischemia-reperfusion injury.Ann Thorac Surg,1998;65(2):439-443.
[44].Meldrum DR,Meng X,Dinarello CA,et al.Human myocardial tissue TNF alpha expressionfollowing acute global ischemia in viva.J Mot Cell Cardiol,1998:30(9):1683-1689.
[45].Kapadia S,Lee J,Torre-Amione G,et al.Tumor necrosis factory gene an dprotein expression in adult feline myocardium after endotoxin administration.J Clin Invest,1995;96:1042-1052.
[46].Donnahoo KK,Shames BD,Harken AH,et al.Review article:the role of tumor necrosis factor in renal isehemia-reperfusion injury.J Urol,1999:162(1):196-203.
[47].Stangl V,Baumann G,Stangl K,et al.Negativeinotropic mediators released from the heart after myocardial ischemia reperfusion.Cardiovasc Res,2002;53:12-30.
[48].汪斌.肿瘤坏死因子与心肌缺血再灌注损伤.国外医学·外科学分册,2001;28(4):200-202.
[49].Yao YM,Yu Y,Wu Y,et al.The role of gut as a cytokine-generating organ in remote organ dysfunction after intestinal ischemia and reperfusion.Chin Med J,1998;111(6):514-518.
[50].金伯泉,赵修行,王成济,等.细胞和分子免疫学.世界图书出版社,1995:129-132.
[51].PatriCPK DA,Moore EE,Moore FA,et al.Lipid mediators upregulate CD11b and prime for concordant superoxide and elastase release in human neutrophils.J Trauma,1997;43:297-303.
[52].Gurevitch J,Frolkis I,Yuhas Y,et al.Anti-tumor necrosis factor alpha improves myocardial recovery after ischemia and reperfusion.J Am Coil Cardiol,1997;30:1554-1561.
[53].Maass DL,White J,Horton J W.IL 1 beta and IL 6 act synergistically with TNF-alpha to alter cardiac contractile function after bum trauma.ShoCPK,2002;18(4):360-366.
[54].Henriksen PA,Newby DE.Therapeutic inhibition of tumor necrosis factoralpha inpatients with heart failure:cooling an inflamed heart,Heart,2003:89(1):14-18.
[55].Communal C,Sumandea M,Solaro JR,et al.Functional consequences of apoptosis in cardiac myocytes:Myofibrillar proteins are targets for caspase-3.Circulation,2001;104:16-21.
[56].Communal.C,Sumandea M,de Tombe P,et al.Functional consequences of caspase activation in cardiac myocytes.Proc Natl Acad Sci USA,2002;99(9):6252-6256
[57].Suzuki K,Murtuza B,Smolenski RT,et al.Overexpression of interleukin-1receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis.Circulation,2001:104(1):1308-1313.
[58].Ono K,Matsumod A,Shioi T,et al.Cytokine gene expression after myocardial infarction in rat heart:possible implication in left ventricular remodeling.Circulation,1998;98:149-156.
[59].Finkel MS,Oddis CV,Jacob TD,et al.Negative inotropic effects of cytokines on the heart mediated by nitric oxide.Science,1992;257:387-389.
[60].Jang IK,Pharm D,Gilber J,et al.Nuclear factor kappa B:Important transcription factor and therapeutic target.J Clinic Pharm,1998;38(6):981-993.
[61].Balakwell TS,Chrisman JW,Gilber J,et al.The role of nuclear factor-IκBα in cytokines gene regulation.Am J Respir Cell Mol Biol,1997;17(1):3-9.
[62].Cain BS,Harken AH,Meldrum DR.Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression hollowing ischemia and reperfnsion.Moll Cell Cardiol,1999;31(5):931-937.
[63].李俊峡,吕泽平,贾国良.心肌缺血再灌注中心肌细胞凋亡的研究进展.心脏杂志,2002;14(4):352-354.
[64].Gottlieb RA,Burleson KO,Kloner RA,et al.Reperfusion injury induces apoptosis in rabbit cardiomyomycytes.J Clin Invest,1994;94(4):1621-1628.
[65].吕泽平,李俊峡,贾国良.心脏疾病与心肌细胞凋亡研究进展.临床荟萃,2002;17(4):237-238.
[66].Saraste A.Apoptosis in human acute myocardial infarction.Circulation,1997;95:320-323.
[67].Von Harsdorf R,Li PF,Diieta:R,et al.Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis.Circulation,1999;99:2934-2941.
[68].Yang BC,Zander DS,Mehta.JL,et al.Hypoxia reoxygenation induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta(1).J Phanmacol Exp Ther,1999:291:733-738.
[69].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. Ca rdiovasc Res, 2000; 45:671 -678.
[70]. Olivetti G, Quaini J, Sala R,et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving protion of the heart. I Mof Cell Cardiol, 1996; 28:2005-2016.
[71]. Vaux DL. Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci USA, 1993;90: 786-792.
[72]. Qin F, Shite J. Mao W, et al. Selegiline atenuates cardiac oxidative stress and apoptosis in heart failure:association with improvement of cardiac function. Eur J Pharmacol, 2003; 461(3):149-158.
[73]. Hofstaetter B, Taimor GS, Inserte J, et al. Inhibition of apoptotic responses after ischemic stress in isolated hearts and cardiomyocytes. Basic-Res-Cardiol, 2002;97(6):479-488.
[74]. 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 heart with myocardial infarction. Circulation, 1996; 94: 1056-1512.
[75]. Hochenbery DM, Oitval ZN, Yin XM, et al.Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell, 1993:85: 241-248.
[76]. Liu P, Xu B, CavalieriTA, HoCPK CE. Age-related diference in myocardial function and inflammation in a rat model of myocardial ischemia-reperfusion.Cardiovasc Res, 2002; 56(3):443-453.
[77]. Hochhauser E, Kivity S, Offen D, et al. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am-J-Physiol-Heart-Circ-Physiol,2003;284(6):H2351-2359.
[78]. Chang TH, Liu XY, Zhang XH, et al .Efects of dl-praeruptorin A on interleukin-6 level and Fas, bax, bcl-2 protein expression in ischemia-reperfusion myocardium.Acta Pharmacol Sin, 2002;(9):769-774.
[79]. Brocheriou V, Hagege AA, Oubenaissa A, et al. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury[J].J Gene Med,2000,2(5):326-333.
[80].朱彪,薛张刚,蒋豪.粘附分子和心肌缺血再灌注损伤的新进展.国外医学·麻醉学与复苏分册,2003;24(3):167-170.
[81].Welboum R,Goldman G,Kobzik L,et al.Role of neutrophil adherence receptors(CD18) in lung permeability hollowing lower torso ischemia.Circ Res,1992;71(1):82-86.
[82].黄兵,左明章.细胞粘附分子与心肌缺血再灌注损伤.国外医学·生理病理科学与临床分册,2001;21(3):195-197.
[83].Fliss H,Gattinger D.Apoptosis in ischemic and reperfused rat myocardium.Cire Res,1996;9:949-956.
[84].Tomioka H,Shimizu T,Maw W,et al.Roles of tumour necrosis factor-alpha(TNF-alpha),transforming growth factor-beta(TGF-beta),and IL-10in the modulation of intercellular adhesion molecule-2(ICAM-1)expression by macrophages during mycobacterial infection.Clinical and Experimental Immunology,2000;122(3):335-342.
[85].Briaud SA,Ding ZM,Michael LH,et al.Leukocyte traffiCPKing and myocardial reperfusion injury in ICAM-1/P-selectin-knoCPKout mice.Am J Physiol Heart Circ Physiol,2001;280(1):H60-H67.
[86].Smith CW,Entman ML,Lane CL,et al.Adherence of neutrophils to canine cardiacmyocytes in vitro is dependent on intercellular adhesion molecule-1.J Clinlnvest,1991;88(4):1216-1223.
[87].Yoshimoto T.The expression of ICAM-1 and Cytokinesin the reperfusional state.Hokkaido Igaku Zasshi,1997;(1):97-103.
[88].Hess DC,Zhao W,Carroll A,et al.Increased expression of ICAM-1 during reoxygenation in brain endothelial cells.Stroke,1994;25:1463-1469.
[89].Seekamp A,Warren JS,RemiCPK DG,et al.Requirements for tumor necrosis factor-alpha and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury.Am J Pathol,1993;143:453-459.
[90].Niessen HW,Krijnen PA,Visser CA,et al.Intercellular adhesion molecule-1 in the heart.Ann N Y Acad Sci,2002;97(3):573-585.
[91].Inculano M,Squadrito F,Altavilla D,et al.Antibodies against intercellular adhesion molecule 1 protect against myocardial ischemia-reperfusion injury in rat.Eur J Pharrnacol,1994;264(2):143-149.
[92].Beauchamp P,Richard V,Tamion F,et al.Protective effects of preconditioning in cultured rat endothelial cells:effects on neutrophil adhesion and expression of ICAM-1 after anoxia and reoxygenation.Circulation,1999;100(5):541-546.
[93].Wang NP,Bufkin BL,Nakamura M,et al.Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis.Ann Thorac Surg,1999;67(6):1689-1695.
[94].Yansaki Y,Matsuura N,Shozuhara H,et al.Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats.Stroke,199:26(4):676-680.
[95].Neurath MF,BeCPKer C,Barbulescu K.Role of NF-kappa B in immune and inflammatory responses in the gut.GUT,1998;43(6):856-860.
[96].冉掌力.心肌缺血预处理延迟保护作用的实验研究.心肺血管病杂志,1999;18(1):59-62.
[97].Chen F,Castranova V,Shi X,Demers LM.New insights into the role of nuclear factor-kappaB,a ubiquitous transcription factor in the initiation of diseases.Clin Chem.1999;45(Ⅰ):7-17.
[98].Schmidt KN,TraenCPKner EBM.Meier B,et al.Induction of oxidative stress by odadaic acid is required for activation of transcription factor NF-κB.J Biol Chem,1995;270(45):27136-27142.
[99].Maekawa N,Wada H,Kanda T,et al.Improved myocardial ischemia/reperfusion injury in mice laCPKing tumor necrosis factor-alpha.J Am Coll Cardiol,2002;39: 1229-1235.
[100]. Arenzana Seisdedos F, Turpin P, Rodriguez M, et al. Nuclear localization of IκB.promotes active transport of NF-kB from the nucleus to the cytoplasm. Cell Sci,1997;110(3):369-378.
[101]. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol, 1994;12:141-179.
[102]. Jang IKL, Pharm D, Gilbert J, et al. Nuclear factor-kappa B: important transcription factor and therapeutic target. J Pharm, 1998; 38(11):981-993.
[103]. Morishita R, Sugimoto T. Aoki M, et al. Invivo transfection of cis element decoy against nuclear factor-kappa B binding site prevents myocardial infarction. Nat Med, 1997;3(8):894-899.
[104]. Elizabeth N, Morgan MD, Edward M. An essential role for NF-κB in the cardioadaptive response to ischemia. Ann Thorac Surg, 1999; 68(2):377-382.
[105]. Engelman DT, Matanabe M, Engelman RM, Rousou JA, Kisin E, Kagom VE,Maulik N, Das DK. Hypoxic preconditioning preserves antioxidant reverse in the working rat heart. Cardiovasc Res 1995; 29(1): 133-140.
[106]. Sharony R, Frolkis I, Froylich D,et al. Pharmacological preconditioning with monophosphoryl lipid A improves postischemic diastolic function and modifies TNF-alpha synthesis. Eur J of Card-thora Surg 2005, (27 ):501-507.
[107]. Prabhakar M.C., Hassina Bano, I. Kumar, et al. Pharmacological investigations on vitexin. J. Medicinal Plant Research 1981; 43:396-403.
[108]. McGee MP, Kreger A, Leake ES, et al. Toxicity of staphylococcal alpha toxin for rabbit alveolar macrophages. Infect Immun 1983; 39(l):439-444.
[109]. Li Q, Shang ZL, Yin JX, et al. Effect of agmatine on intracellular free calcium concentration in isolated rat ventricular myocytes. Acta Physiologica Sinica 2002;54(6):467-472.
[110]. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, et al. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 1993;72:1293-9.
[111]. Przyklenk K, Kloner RA. Ischemic preconditioning: exploring the paradox. Prog Cardiovasc Dis 1998;40:517-47.
[112]. Roberto B. The late phase of preconditioning[J]. Circulation Research, 2000,24:972-983.
[113]. Lum H, Barr DA, Shafer JR. Reoxygenation of endothelial cells increases permeability by oxidant-dependent mechanisms. Circ Res, 1992;70 (5):991-998.
[114]. Xuan YT, Tang XL, Bangerjce S, et al. Nuclear factor kB play an essential role in the phase of ischemic preconditioning in conscious rabbits. Circ Res, 1999,84(9):1095-1109.
[115]. Kawabata KI, Thomas N, Mitsuru O, et al. Mechanisms of ischemic preconditioning effects on Ca~(2+) paradox-induced changes in heart. Am J Physiol, 2000, 278: H1008-H1015.
[116]. Ohtsuka M, Takano H, Suzuki M, et al. Role of Na~+ -Ca~(2+) exchanger in myocardial ischemia / reperfusion injury: evaluation using a heterozygous Na~+-Ca~(2+) exchanger knoCPKout mouse model. Biochem Biophys Res Commun,2004, 314: 849-853.
[117]. Satoh H, Mukai M, Urushida T ,et al. Importance of Ca~(2+) influx by Na~+ /Ca~(2+) exchange under normal and sodium-loaded conditions in mammalian ventricles.Mol Cell Biochem, 2003 , 242 (1-2) : 11-17.
[118]. Strom C, Barancik M, Brahl M, et al. Inhibition of ER-kinase cascade by PD98059 and U0126 counteracts ischemic preconditioning in pig myocardium [J].Cardiovasc Res, 2000,36(2):218-229.
[119]. Liu XH, Wang SW, Wu XD, et al. The role of mitogen-activated protein kinases family in ischemic preconditioning of rat heart[J]. Chinese Medical Journal, 1999,79(7): 542-545.
[1]Maczewki M,Beresewicz A.The role of endothelin,protein kinase C and radicals in the mechanism of the post-ischemic endothelial dysfunction in guinea-pig hearts.J Mol Cardiol,2000,32(2):297-310.
[2]Oshiro Y,Shimabukuro M,Takasu N,et al.Triidothyronine concomitantly inhibits calcium overload and postischemic myocardial stuuning in diabetic rats.Life Sci,2001,69(16):1907-1918.
[3]王凌燕,蔡高军,孙文伟,等.脂质载体前列腺素E_1对大鼠心肌缺血/再灌注损伤的保护作用.中国实验诊断学,2006,10(3):255-257.
[4]Sugano M,Hata T,Tsuchida K,et al.Local delivery of soluble TNF—alpha receptor 1 gene reduces infarct size following ischemia/reperfusionin jury in rats[J].Mol Cel Biochem,2004,266(2):127-132.
[5]Ono K,Matsumori A,Shioi T,et al.Cytokine gene expression after myocardial infarction in rat hearts:possible implication in left ventricular remodeling[J].Circulation,1998,98(2):14-22.
[6]Adams DH,Tilney NL,Colins JJ,et al.Experimental graft arteriosclerosis:I the Lewis-to-F344 allograft model[J].Transplant,-tion,1992,53:1115-1121.
[7]Conover CA,Chen BK,Resch ZT,et al.Regulation of pregnancy-associated plasma p rotein-A expression in cultured human osteoblasts[J].Bone,2004,34(2):297-306.
[8]Beaudeu JL,Burc I,Imbert-Bismut F,et al.Serum pregnancy-associated plasma protein A:a potential merbeir of echogenic carotid atherosclerotic plaques in a symptomatic hyparlipidemic subjects at high cardiovascular risk[J].Artheroscler T hrombo Vase Biol,2003,23:7-16.
[9]沈诚,范士志,陈建明,李志平,等.抑制JAK/STAT通路对缺血再灌注损伤心肌TNF-α和IL-6表达的影响.重庆医学,2006,35(1):38-39.
[10]司良毅,陈运贞.缺血再灌注心肌白介素—2表达和N—乙酞半胱氨酸对损伤 影响的观察[J]第三军医大学学报,2002,24(5):581-584.
[11]ShibataM,E ndoS,In adaK,et al.El evated plasma levels of IL-1 receptor antagonist andI L-10 in patients with acute myocardial infarction[J].Interferon Cytokine Res,1997,17(3):145-148.
[12]李拥军,丁文惠,高炜,等.白介素-1受体拮抗剂对缺血再灌注心肌的保护作用及其机制探讨[J]。中华医学杂志,2004,84(7):548-553.
[13]Merchant SH,Gurule DM,Larson RS,et al.Amelioration of ischemia-reperfusion injury with cyclic peptide bloCPKade of ICAM-1[J].AmJ P hysiolH eartC ircP hysiol,2003,284(4):1260-1268.
[14]Yang XP,Irani K,Mattagajasingh S,et al.Signal Transducer and Activator of Transcription 3 {alpha 1 and Specificity Protein 1 Interact to Upregulate Intercelular Adhesion Molecule-1 in Ischemic-Reperfused Myocardium and Vascular Endothelium[J].Arterioscler Thromb Vasc Biol,2005,28(3);1-3
[15]沈诚,范士志,陈建明,等,中国体外循环杂志,2006,4(1):41-43.
[16]吴付轩,丁文惠,张钧华,等.急性心肌缺血再灌注期间血浆白介素-8的变化和意义[J].中国实用内科杂志,1999,19(9):527-529.
[17]张艳芳,杨廷桐,白细胞介素—1,8,10与心肌缺血一再灌注损伤[J].新乡医学院学报,2006,23(2):210-212.
[18]Krizanac-Bengez L,Kapural M,Parkinson F,et al.Effects of transient loss of shear stress on blood-brain barrier endothelium:role of nitric oxide and IL-6[J].Brain Res,2003,977(2):239-246.
[19]Smith EF 3rd,Egan JW,Bugelski PJ,et al.Temporal relation between neutrophil accumulation and myocardial reperfusion injury,Am J Physiol.1988 Nov;255(5 Pt 2):H1060-1068.
[20]Williams FM,Kus M,Tanda K,et al.Effect of duration of ischaemia on reduction of myocardial infarct size by inhibition of neutrophil accumulation using an anti-CD18 monoclonal antibody.Br J Pharmacol.1994;111(4):1123-1128.
[21]Klimas R,Siminiak T,WysoCPKi H,Neutrophil adherence-augmenting and chemotactic plasma activities in acute myocardial infarction: effect of fibrinolytic treatment, Int J Cardiol. 1993 Dec 31;42(3):239-244.
[22] Bell D, JaCPKson M, Nicoll JJ, et al. Inflammatory response, neutrophil activation, and free radical production after acute myocardial infarction: effect of thrombolytic treatment, Br Heart J. 1990 Feb;63(2):82-87.
[23] Niessen HW, Lagrand WK, Visser CA,,et al. Upregulation of ICAM-1 on cardiomyocytes in jeopardized human myocardium during infarction. Cardiovasc Res. 1999 Mar;41(3):603-610.
[24] Fein AM, Grant MM, Niederman MS, et al. Neutrophil-endothelial cell interaction in critical illness. Chest. 1991 Jun;99(6):1456-1462.
[25] Jones SP, Trocha SD, Strange MB, et al,Tumor necrosis factor mediates E-selectin production of the human heart[J]. Ann Thorac Surg, 2001,71(1):226-232.
[26] Dewald.O, Frangogiannis NG,, Zoerlein MP,,et al. A murine model of ischemic cardiomyopathy induced by repetitive ischemia and reperfusion Thorac Cardiovasc Surg. 2004 Oct;52(5):305-311.
[27] Fishbein MC, Maclean D, Maroko PR, et al. Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution, Am J Pathol. 1978;90(1):57-70.
[28] Romson JL, Hook BG, Kunkel SL,et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation.1983;67(5):1016-1023.
[29] Silver MJ, Sutton JM,, Hook S, et al. Adjunctive selectin bloCPKade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model. Circulation. 1995 ;92(3):492-499.
[30] Frangogiannis NG, Targeting the Inflammatory Response in Healing Myocardial Infarcts[J]. Current Medicinal Chemistry, 2006, 13, 1877-1893.
[31] Frangogiannis NG, Dewald O, Xia Y, et al. Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy, Circulation. 2007 Feb 6;115(5):584-592.
[32] Lahat N, Rabat MA, Ballan M, et al. Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion[ J].J Leukoc Biol,2003,74(2): 197-205.
[33] Kajihara N , Morita S , Nishida T, et al. Transfection with a dominant-negative inhibitor of monocyte chemoattractant protein-1 gene improves cardiac function after 6 hours of cold preservation[J] .Circulation, 2003 ,108 (Suppl 1):213-218.
[34] NakamuraT , Abu-Dahab R, Menger MD, et al. Depletion of alveolar macrophages by clodronate-liposomes aggravates ischemia-reperfusionin jury of the lung[J] J Heart Lung Transplant, 2005,24(1): 38-45.
[35] DaCosta ML, Yao Z, MacPherson BC, et al. Brief hypoxia conditionsm onocytesto p rotectre perfusedc ardiocytesag ainstce llde ath via the CDllb receptor[J].J Heart Lung Transplant, 2003, 22(9) ;979-985.
[36] Ito H, Nakano A, Kinoshita M, et al.Pioglitazone, a peroxiaome proliferator receptor-gamma agonist, attenuates myocardial ischemia/reperfusion injury in a rat model[J]. Lab Invest, 2003,83(12):1715-1720.
[37] Yue TL,Chen J, Bao W, et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone[J]. Circulation, 2001,104(21):2588-2590.
[38] Bhattacharya K, Farwell K, Huang M, Mast cell deficient W/Wv mice have lower serum IL-6 and less cardiac tissue necrosis than their normal littermates following myocardial ischemia-reperfusionlnt J Immunopathol Pharmacol. 2007 Jan-Mar;20(l):69-74.
[39] LiuYH, YangXP, MehtaD, et al. Role of kininsin chronic heart failure and in the therapeutic effect of ACE inhibitorsin kininogen-deficient rats[J]. Am J Physiol Heart Circ Physiol, 2000,278(2): H507-H514.
[40] Lazar HL, Bao Y, Rivers S, et al. Pretreatment with angiotensin converting enzyme inhibitors attenuates ischemia-reperfusion injury[J]. Ann Thorac Surg, 2002,73(5):1522-1527.
[41]Wang LX,Ideishi M,Yahiro E,et al.Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia reperfusion induced myocardial injury[J].Hypertens Res,2001,24(2):179-187.
[42]Kumari R,Maulik M,Manchanda SC,et al;Protective effect of bradykin in antagonist Hoe-140 during in vivo mycocardial ischemic-reperfusion injury in the cat[J].Regul Pept.2003,115(3):211-218.
[43]崔少波,赵学森,崔涛,等,缓激肽在苯那普利抗大鼠心肌缺血再灌注损伤中的作用,中国误诊学杂志 2006,16(8):1428-1430.
[44]Chun-Yang Xiao,Akiyoshi Hara,Koh-ichi Yuhki,Ischemia-Reperfusion Injury:A Study Using Mice LaCPKing Their Respective Roles of Prostaglandin I2 and Thromboxane A2 in Cardiac Receptors.Circulation 2001;104;2210-2215.
[45]Calabresi L,Rossoni G,Gomaraschi M,et al.High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-α content and enhancing prostaglandin release[J].Circ Res.2003;92:330-337.
[46]Chun-Yang Xiao,Koh-ichi Yuhki,Akiyoshi Hara,et al.Prostaglandin E2 Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP 4[J].Circulation 2004;109;2462-2468.
[47]Boli R,Shinmura K,Tang XL,et al,Discovery of a new function of cycloxygenase(COX-2):COX-2 is a cardiopretective protein in that aleviates ischemial/reperfusion injury and mediate the late phase of preconditioning[J].Cardiovasc Res,2002,55(3):506-519.
[48]Saito T,Rodger IW,Hu F,et al.Inhibition of cyclooxygenase-2 imoproves cardiac function in myocardiac infarction.[J].Biochem Biophys Res Commun,2000,273(2):772-775.
[49]Scheurenn N,Jochbs M,Ertl G,et al,Cyclooxygenase-2 in myocardiam stimulation by angiotensin-Ⅱ in cultured fibroblasts and role acute mvocardial infarction.[J] J Mol Cell Cardiol, 2002,34(l):29-37.
[50] Saito T, Rodger IW, Hu F, et al, Inhibition of COX pathway in experimental myocardial infarction [J]. J Mol Cell Cardiol, 2004,37(1):71-77.
[51] O'Shea, J.J. et al. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell, 2002,109 (Suppl), S121-S131.
[52] Levy, D.E, Darnell, J.E., Jr .Stats: transcriptional control and biological impact. Nat.Rev. Mol. Cell Biol. 2002,3: 651-662.
[53] Negoro, S. et al. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc. Res. 2002,47:797-805.
[54] Kunisada, K. et al. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc. Natl. Acad. Sci. 2000,97:315-319.
[55] Negoro, S. et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenationinduced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 2001,104:979-981.
[56] Oshima, Y. et al. STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc. Res. 2005, 65:428-435
[57] Hilfiker-Kleiner, D. et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition,and heart protection from ischemic injury. Circ. Res. 2004,95:187-195.
[58] Stephanou, A. et al. Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J. Biol. Chem. 2000,275:10002-10008.
[59] McCormiCPK, J. et al. Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury. FASEB J. 2006,20:2115-2117.
[60] Xuan, Y.T. et al. Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J. Mol. Cell. Cardiol. 2003, 35:525-537.
[61] Xuan, Y.T. et al. An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc. Natl. Acad. Sci. 2001, 98:9050-9055.
[62] Hernandez Gutierrez S, Rojas del Castillo E. Role of the transcription factor NF-kappaB in the cardiac cell. Arch Cardiol Mex. 2005 Jul-Sep;75(3):363-370.
[63] Tillmanns J, Carlsen H, Blomhoff R, et al. Caught in the act: in vivo molecular imaging of the transcription factor NF-kappaB after myocardial infarction. Biochem Biophys Res Commun. 2006 Apr 14;342(3):773-774.
[64] Lu L, Chen SS, Zhang JQ, et al. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun. 2004 Sep 3;321(4):879-885.
[65] Kawamura N, Kubota T, Kawano S, et al, BloCPKade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy. Cardiovasc Res. 2005 ;66(3):520-529.
[66] Kawano S, Kubota T, Monden Y, et al, BloCPKade of NF-kappaB improves cardiac function and survival after myocardial infarction. Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1337-344.
[2].Sekikawa,Horiuchi,Edmundowicz,et al.A "natural experiment" incardiovascular epidemiology in the early 21st century.Heart,2003;89:255-257.
[3].Maxwell SR,Lip GY.Reperfusion injury:a review of the pathophysiology,clinical manifestations and therapeutic options.Int J Cardiol,1997;58:95-117.
[4].Piper HM,et al.Afresh look at reperfusion injury.Cardiovas Res,1998;38:291-300.
[5].Bolli R.Basic and clinical aspects of myocardial stunning.Prog Cardiovas Dis,1998;40:477-516.
[6].PAJ Krijnen,R Nijmeijer,CJLM Meijer,et al.Apoptosis in myocardial ischaemia and infarction.J Clin Pathol,2002;55:801-811.
[7].Fliss H.Apoptosis in ischemic and reperfused rat myocardium.Circ Res,1996;79:949-956.
[8].Piot CA.Ischemic preconditioning decrease apoptosis in rat heart in vivo.Circulation,1997;96:1598-1604.
[9].Zhao ZQ,Nakamura M,Wang Nf,et al.Reperfusion induces myocardial apoptotic cell death.Cardiovasc Res,2000;45:651-660.
[10].Murry CE,Jennings RB,Reimer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium.Circulation 1986;74:1124-36.
[11].许正斌,高奎斌,许双贵.山楂叶综述[J].中医药学报,1985,4:49-50.
[12].斯建勇,陈迪华,高兴跃.云南山楂叶化学成分的研究[J].中国中药杂志,1998,23(7):422-424.
[13].叶希韵,王耀发.山楂叶总黄酮对血管内皮细胞氧化损伤的保护作用[J].中国现代应用药学杂志,2002,19(4):265-267.
[14].后德辉.一种简便的抗心肌缺氧药物筛选方法.蚌埠医学院学报,1998,23 (6):372-374
[15].王玉梅,刘兴君,王敏伟.赞丹松口服液对实验性心肌缺血的影响.中国民族医学杂志,2002,8(3):37-38
[16].朱玲,蔡绍辉,刘于宾,等.金泽冠心胶囊药效学实验研究.华西药学杂志,2000,15(6):428-429
[17].徐叔云,卞如濂,陈修主编.药理实验方法学(第三版),北京:人民卫生出版社,2002:1052-1054
[18].张英,李著华,王顺蓉,等.杏丁预处理对实验性兔急性心肌缺血的保护作用.中国煤炭工业医学杂志,2002,5(5):508-509
[19].Banai S,Jaklitsch MT,Shou M,et al.Angiogenic induced enhance mentofcol lateral blood flow to is chmicmy cardium by VEGF in dogs[J].Circulation,1994,25(9):530-532.
[20].陈铎葆,刘建国,管云风,等.红花黄素Ⅲ对犬缺血心肌的影响[J].中国药理学通报,2000,16(5):590-591.
[21]..徐叔云,卞如濂,陈修主编.药理实验方法学(第三版),北京:人民卫生出版社,2002:1054.
[22].于占久,王炳璋,杨鸣岗,等.关于心肌梗死的实验研究Ⅰ—动物模型的建立及心外膜电图标测术[J].中华心血管病杂志,1980,8(1):65-67.
[23].徐叔云,卞如濂,陈修主编.药理实验方法学(第三版),北京:人民卫生出版社,2002:1283-1284
[24].Rahimi AR,Marzano PM 3rd,Richard CM.Evaluation of lactate and C-reactive protein in the assessment of acute myocardial infarction[J].South Med J,2003;96(11):1107-1112.
[25].Juarez U,Trejo W,Whente M,et al.The usefulness of determining myoglobin,creatine ph0sphokinase MB isoenzyme,lactate dehydrogenase and aspartate aminotransferase in the diagnosis of acute myocardial infart[J].Arch Inst Cardiol Mex,1998;68(3):214-217.
[26].HaCPKenbroCPK CPK,Baue AE,Johnson D,et al.Lateral diffusion and electron tranfer in the mitochondrial inner membrane[J].Trends Biochem Sci,1998;6:151-158.
[27].Slater EC,Toda K,Kayano K,et al.A hypothesis for the mechanism of respiratory chain phosphorylation not involving the electrochemical gradient of protons as obligatory intermedicate[J].Biochem Biophys Acta,1995;8:211-217.
[28].叶萍仙,朱建华,夏强.脂质体携载前列腺素El抗心肌缺血再灌注损伤.中国药理学通报,2001;17(3):302-305.
[29].Lenen S,Gorlich JK,RustenbeCPK I,et al.Regulation of transmembrane in transport by reaction products of phospholipase as infects of lypiphospholipilid on mitochondrial Ca~(2+) transport[J].Biochem Biophys Acta,1999;982:140-146.
[30].Salvatore Cuzzocrea,Dennis P.Riley,Achille P.Caputi and Daniela Salvemini.Antioxidant Therapy:A New Pharmacological Approach In ShoCPK,Inflammation,and Ischemia/Reperfusion Injury.Pharmacological Reviews,2001,53(1):135-159.
[31].Dart RC,Sanders AB.Oxygen free radicals and myocardial reperfusion injury.,Ann Emerg Med,1988;17(1):53-58.
[32].Flitter WD.Free radicals and myocardial reperfusion injury.Br Med Bull 1993;49(3):545-555.
[33].McLeod LL,Sevanian A.Lipid peroxidation and modification of lipid composition in an endothelial cell model of ischemia and reperfusion.Free Radic Biol Med,1997;23(4):680-694.
[34].Hillis LD,Braunwald E.Myocardial ischemia.New Rngl Med,1977;296(18):1034-1041.
[35].范丽,郭岩,陈志武,等.黄蜀葵花总黄酮保护离体大鼠心肌缺血再灌注损伤的研究[J].中国药理学通报,2003,19(2):191-193.
[36].Holmberg SR,Cunmming DV,Kusarna Y,et al.Reactive oxygen species midify the structure and function of the cardiac sarcoplasmic reticulum calcium channel[J].Cardio Science,1991,2:19-25.
[37].Goldhaber JI,Ji S,Lamp ST,Weiss JN.Effects of exogenous free radicals onelectromechanical function and metabolism in isolated rabbit and guinea pig ventricle:implications for ischemia and reperfusion injury[J].J Clin Invest,1988,83(6):180-189.
[38].Scott Kinlay,Peter Ganz.Role of endothelial dysfunction in coronary artery disease and implications for therapy[J].Am J Cardiol,1997;80(9A):11I-6I.
[39].Nikolaos GF,Smith CW,Mark LE.The inflammatory response in myocardial infarction[J].Cardiovasc Res,2002,53(1):31-47.
[40].徐叔云,卞如濂,陈修等.药理学方法学(第三版),北京:人民卫生出版社,2002:987-989.
[41].Ozmen L,Aguet M.The in vivo antiviral activity of interleukin-12 is mediated by Gamma interferon.J Virology,1995,69:8147.
[42].Frangogiannis NG,Smith CW,Entman M.The inflammatory response in myocardial infarction.Cardiovasc Res,2002;53(1):31-47.
[43].Meldrum DR,Cleveland JC Jr,Cain BS,et al.Increased myocardial tumor necrosis factor alpha in a crystalloid perfused model of cardiac ischemia-reperfusion injury.Ann Thorac Surg,1998;65(2):439-443.
[44].Meldrum DR,Meng X,Dinarello CA,et al.Human myocardial tissue TNF alpha expressionfollowing acute global ischemia in viva.J Mot Cell Cardiol,1998:30(9):1683-1689.
[45].Kapadia S,Lee J,Torre-Amione G,et al.Tumor necrosis factory gene an dprotein expression in adult feline myocardium after endotoxin administration.J Clin Invest,1995;96:1042-1052.
[46].Donnahoo KK,Shames BD,Harken AH,et al.Review article:the role of tumor necrosis factor in renal isehemia-reperfusion injury.J Urol,1999:162(1):196-203.
[47].Stangl V,Baumann G,Stangl K,et al.Negativeinotropic mediators released from the heart after myocardial ischemia reperfusion.Cardiovasc Res,2002;53:12-30.
[48].汪斌.肿瘤坏死因子与心肌缺血再灌注损伤.国外医学·外科学分册,2001;28(4):200-202.
[49].Yao YM,Yu Y,Wu Y,et al.The role of gut as a cytokine-generating organ in remote organ dysfunction after intestinal ischemia and reperfusion.Chin Med J,1998;111(6):514-518.
[50].金伯泉,赵修行,王成济,等.细胞和分子免疫学.世界图书出版社,1995:129-132.
[51].PatriCPK DA,Moore EE,Moore FA,et al.Lipid mediators upregulate CD11b and prime for concordant superoxide and elastase release in human neutrophils.J Trauma,1997;43:297-303.
[52].Gurevitch J,Frolkis I,Yuhas Y,et al.Anti-tumor necrosis factor alpha improves myocardial recovery after ischemia and reperfusion.J Am Coil Cardiol,1997;30:1554-1561.
[53].Maass DL,White J,Horton J W.IL 1 beta and IL 6 act synergistically with TNF-alpha to alter cardiac contractile function after bum trauma.ShoCPK,2002;18(4):360-366.
[54].Henriksen PA,Newby DE.Therapeutic inhibition of tumor necrosis factoralpha inpatients with heart failure:cooling an inflamed heart,Heart,2003:89(1):14-18.
[55].Communal C,Sumandea M,Solaro JR,et al.Functional consequences of apoptosis in cardiac myocytes:Myofibrillar proteins are targets for caspase-3.Circulation,2001;104:16-21.
[56].Communal.C,Sumandea M,de Tombe P,et al.Functional consequences of caspase activation in cardiac myocytes.Proc Natl Acad Sci USA,2002;99(9):6252-6256
[57].Suzuki K,Murtuza B,Smolenski RT,et al.Overexpression of interleukin-1receptor antagonist provides cardioprotection against ischemia-reperfusion injury associated with reduction in apoptosis.Circulation,2001:104(1):1308-1313.
[58].Ono K,Matsumod A,Shioi T,et al.Cytokine gene expression after myocardial infarction in rat heart:possible implication in left ventricular remodeling.Circulation,1998;98:149-156.
[59].Finkel MS,Oddis CV,Jacob TD,et al.Negative inotropic effects of cytokines on the heart mediated by nitric oxide.Science,1992;257:387-389.
[60].Jang IK,Pharm D,Gilber J,et al.Nuclear factor kappa B:Important transcription factor and therapeutic target.J Clinic Pharm,1998;38(6):981-993.
[61].Balakwell TS,Chrisman JW,Gilber J,et al.The role of nuclear factor-IκBα in cytokines gene regulation.Am J Respir Cell Mol Biol,1997;17(1):3-9.
[62].Cain BS,Harken AH,Meldrum DR.Therapeutic strategies to reduce TNF-alpha mediated cardiac contractile depression hollowing ischemia and reperfnsion.Moll Cell Cardiol,1999;31(5):931-937.
[63].李俊峡,吕泽平,贾国良.心肌缺血再灌注中心肌细胞凋亡的研究进展.心脏杂志,2002;14(4):352-354.
[64].Gottlieb RA,Burleson KO,Kloner RA,et al.Reperfusion injury induces apoptosis in rabbit cardiomyomycytes.J Clin Invest,1994;94(4):1621-1628.
[65].吕泽平,李俊峡,贾国良.心脏疾病与心肌细胞凋亡研究进展.临床荟萃,2002;17(4):237-238.
[66].Saraste A.Apoptosis in human acute myocardial infarction.Circulation,1997;95:320-323.
[67].Von Harsdorf R,Li PF,Diieta:R,et al.Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis.Circulation,1999;99:2934-2941.
[68].Yang BC,Zander DS,Mehta.JL,et al.Hypoxia reoxygenation induced apoptosis in cultured adult rat myocytes and the protective effect of platelets and transforming growth factor-beta(1).J Phanmacol Exp Ther,1999:291:733-738.
[69].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. Ca rdiovasc Res, 2000; 45:671 -678.
[70]. Olivetti G, Quaini J, Sala R,et al. Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving protion of the heart. I Mof Cell Cardiol, 1996; 28:2005-2016.
[71]. Vaux DL. Toward an understanding of the molecular mechanisms of physiological cell death. Proc Natl Acad Sci USA, 1993;90: 786-792.
[72]. Qin F, Shite J. Mao W, et al. Selegiline atenuates cardiac oxidative stress and apoptosis in heart failure:association with improvement of cardiac function. Eur J Pharmacol, 2003; 461(3):149-158.
[73]. Hofstaetter B, Taimor GS, Inserte J, et al. Inhibition of apoptotic responses after ischemic stress in isolated hearts and cardiomyocytes. Basic-Res-Cardiol, 2002;97(6):479-488.
[74]. 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 heart with myocardial infarction. Circulation, 1996; 94: 1056-1512.
[75]. Hochenbery DM, Oitval ZN, Yin XM, et al.Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell, 1993:85: 241-248.
[76]. Liu P, Xu B, CavalieriTA, HoCPK CE. Age-related diference in myocardial function and inflammation in a rat model of myocardial ischemia-reperfusion.Cardiovasc Res, 2002; 56(3):443-453.
[77]. Hochhauser E, Kivity S, Offen D, et al. Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice. Am-J-Physiol-Heart-Circ-Physiol,2003;284(6):H2351-2359.
[78]. Chang TH, Liu XY, Zhang XH, et al .Efects of dl-praeruptorin A on interleukin-6 level and Fas, bax, bcl-2 protein expression in ischemia-reperfusion myocardium.Acta Pharmacol Sin, 2002;(9):769-774.
[79]. Brocheriou V, Hagege AA, Oubenaissa A, et al. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury[J].J Gene Med,2000,2(5):326-333.
[80].朱彪,薛张刚,蒋豪.粘附分子和心肌缺血再灌注损伤的新进展.国外医学·麻醉学与复苏分册,2003;24(3):167-170.
[81].Welboum R,Goldman G,Kobzik L,et al.Role of neutrophil adherence receptors(CD18) in lung permeability hollowing lower torso ischemia.Circ Res,1992;71(1):82-86.
[82].黄兵,左明章.细胞粘附分子与心肌缺血再灌注损伤.国外医学·生理病理科学与临床分册,2001;21(3):195-197.
[83].Fliss H,Gattinger D.Apoptosis in ischemic and reperfused rat myocardium.Cire Res,1996;9:949-956.
[84].Tomioka H,Shimizu T,Maw W,et al.Roles of tumour necrosis factor-alpha(TNF-alpha),transforming growth factor-beta(TGF-beta),and IL-10in the modulation of intercellular adhesion molecule-2(ICAM-1)expression by macrophages during mycobacterial infection.Clinical and Experimental Immunology,2000;122(3):335-342.
[85].Briaud SA,Ding ZM,Michael LH,et al.Leukocyte traffiCPKing and myocardial reperfusion injury in ICAM-1/P-selectin-knoCPKout mice.Am J Physiol Heart Circ Physiol,2001;280(1):H60-H67.
[86].Smith CW,Entman ML,Lane CL,et al.Adherence of neutrophils to canine cardiacmyocytes in vitro is dependent on intercellular adhesion molecule-1.J Clinlnvest,1991;88(4):1216-1223.
[87].Yoshimoto T.The expression of ICAM-1 and Cytokinesin the reperfusional state.Hokkaido Igaku Zasshi,1997;(1):97-103.
[88].Hess DC,Zhao W,Carroll A,et al.Increased expression of ICAM-1 during reoxygenation in brain endothelial cells.Stroke,1994;25:1463-1469.
[89].Seekamp A,Warren JS,RemiCPK DG,et al.Requirements for tumor necrosis factor-alpha and interleukin-1 in limb ischemia/reperfusion injury and associated lung injury.Am J Pathol,1993;143:453-459.
[90].Niessen HW,Krijnen PA,Visser CA,et al.Intercellular adhesion molecule-1 in the heart.Ann N Y Acad Sci,2002;97(3):573-585.
[91].Inculano M,Squadrito F,Altavilla D,et al.Antibodies against intercellular adhesion molecule 1 protect against myocardial ischemia-reperfusion injury in rat.Eur J Pharrnacol,1994;264(2):143-149.
[92].Beauchamp P,Richard V,Tamion F,et al.Protective effects of preconditioning in cultured rat endothelial cells:effects on neutrophil adhesion and expression of ICAM-1 after anoxia and reoxygenation.Circulation,1999;100(5):541-546.
[93].Wang NP,Bufkin BL,Nakamura M,et al.Ischemic preconditioning reduces neutrophil accumulation and myocardial apoptosis.Ann Thorac Surg,1999;67(6):1689-1695.
[94].Yansaki Y,Matsuura N,Shozuhara H,et al.Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats.Stroke,199:26(4):676-680.
[95].Neurath MF,BeCPKer C,Barbulescu K.Role of NF-kappa B in immune and inflammatory responses in the gut.GUT,1998;43(6):856-860.
[96].冉掌力.心肌缺血预处理延迟保护作用的实验研究.心肺血管病杂志,1999;18(1):59-62.
[97].Chen F,Castranova V,Shi X,Demers LM.New insights into the role of nuclear factor-kappaB,a ubiquitous transcription factor in the initiation of diseases.Clin Chem.1999;45(Ⅰ):7-17.
[98].Schmidt KN,TraenCPKner EBM.Meier B,et al.Induction of oxidative stress by odadaic acid is required for activation of transcription factor NF-κB.J Biol Chem,1995;270(45):27136-27142.
[99].Maekawa N,Wada H,Kanda T,et al.Improved myocardial ischemia/reperfusion injury in mice laCPKing tumor necrosis factor-alpha.J Am Coll Cardiol,2002;39: 1229-1235.
[100]. Arenzana Seisdedos F, Turpin P, Rodriguez M, et al. Nuclear localization of IκB.promotes active transport of NF-kB from the nucleus to the cytoplasm. Cell Sci,1997;110(3):369-378.
[101]. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol, 1994;12:141-179.
[102]. Jang IKL, Pharm D, Gilbert J, et al. Nuclear factor-kappa B: important transcription factor and therapeutic target. J Pharm, 1998; 38(11):981-993.
[103]. Morishita R, Sugimoto T. Aoki M, et al. Invivo transfection of cis element decoy against nuclear factor-kappa B binding site prevents myocardial infarction. Nat Med, 1997;3(8):894-899.
[104]. Elizabeth N, Morgan MD, Edward M. An essential role for NF-κB in the cardioadaptive response to ischemia. Ann Thorac Surg, 1999; 68(2):377-382.
[105]. Engelman DT, Matanabe M, Engelman RM, Rousou JA, Kisin E, Kagom VE,Maulik N, Das DK. Hypoxic preconditioning preserves antioxidant reverse in the working rat heart. Cardiovasc Res 1995; 29(1): 133-140.
[106]. Sharony R, Frolkis I, Froylich D,et al. Pharmacological preconditioning with monophosphoryl lipid A improves postischemic diastolic function and modifies TNF-alpha synthesis. Eur J of Card-thora Surg 2005, (27 ):501-507.
[107]. Prabhakar M.C., Hassina Bano, I. Kumar, et al. Pharmacological investigations on vitexin. J. Medicinal Plant Research 1981; 43:396-403.
[108]. McGee MP, Kreger A, Leake ES, et al. Toxicity of staphylococcal alpha toxin for rabbit alveolar macrophages. Infect Immun 1983; 39(l):439-444.
[109]. Li Q, Shang ZL, Yin JX, et al. Effect of agmatine on intracellular free calcium concentration in isolated rat ventricular myocytes. Acta Physiologica Sinica 2002;54(6):467-472.
[110]. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, et al. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 1993;72:1293-9.
[111]. Przyklenk K, Kloner RA. Ischemic preconditioning: exploring the paradox. Prog Cardiovasc Dis 1998;40:517-47.
[112]. Roberto B. The late phase of preconditioning[J]. Circulation Research, 2000,24:972-983.
[113]. Lum H, Barr DA, Shafer JR. Reoxygenation of endothelial cells increases permeability by oxidant-dependent mechanisms. Circ Res, 1992;70 (5):991-998.
[114]. Xuan YT, Tang XL, Bangerjce S, et al. Nuclear factor kB play an essential role in the phase of ischemic preconditioning in conscious rabbits. Circ Res, 1999,84(9):1095-1109.
[115]. Kawabata KI, Thomas N, Mitsuru O, et al. Mechanisms of ischemic preconditioning effects on Ca~(2+) paradox-induced changes in heart. Am J Physiol, 2000, 278: H1008-H1015.
[116]. Ohtsuka M, Takano H, Suzuki M, et al. Role of Na~+ -Ca~(2+) exchanger in myocardial ischemia / reperfusion injury: evaluation using a heterozygous Na~+-Ca~(2+) exchanger knoCPKout mouse model. Biochem Biophys Res Commun,2004, 314: 849-853.
[117]. Satoh H, Mukai M, Urushida T ,et al. Importance of Ca~(2+) influx by Na~+ /Ca~(2+) exchange under normal and sodium-loaded conditions in mammalian ventricles.Mol Cell Biochem, 2003 , 242 (1-2) : 11-17.
[118]. Strom C, Barancik M, Brahl M, et al. Inhibition of ER-kinase cascade by PD98059 and U0126 counteracts ischemic preconditioning in pig myocardium [J].Cardiovasc Res, 2000,36(2):218-229.
[119]. Liu XH, Wang SW, Wu XD, et al. The role of mitogen-activated protein kinases family in ischemic preconditioning of rat heart[J]. Chinese Medical Journal, 1999,79(7): 542-545.
[1]Maczewki M,Beresewicz A.The role of endothelin,protein kinase C and radicals in the mechanism of the post-ischemic endothelial dysfunction in guinea-pig hearts.J Mol Cardiol,2000,32(2):297-310.
[2]Oshiro Y,Shimabukuro M,Takasu N,et al.Triidothyronine concomitantly inhibits calcium overload and postischemic myocardial stuuning in diabetic rats.Life Sci,2001,69(16):1907-1918.
[3]王凌燕,蔡高军,孙文伟,等.脂质载体前列腺素E_1对大鼠心肌缺血/再灌注损伤的保护作用.中国实验诊断学,2006,10(3):255-257.
[4]Sugano M,Hata T,Tsuchida K,et al.Local delivery of soluble TNF—alpha receptor 1 gene reduces infarct size following ischemia/reperfusionin jury in rats[J].Mol Cel Biochem,2004,266(2):127-132.
[5]Ono K,Matsumori A,Shioi T,et al.Cytokine gene expression after myocardial infarction in rat hearts:possible implication in left ventricular remodeling[J].Circulation,1998,98(2):14-22.
[6]Adams DH,Tilney NL,Colins JJ,et al.Experimental graft arteriosclerosis:I the Lewis-to-F344 allograft model[J].Transplant,-tion,1992,53:1115-1121.
[7]Conover CA,Chen BK,Resch ZT,et al.Regulation of pregnancy-associated plasma p rotein-A expression in cultured human osteoblasts[J].Bone,2004,34(2):297-306.
[8]Beaudeu JL,Burc I,Imbert-Bismut F,et al.Serum pregnancy-associated plasma protein A:a potential merbeir of echogenic carotid atherosclerotic plaques in a symptomatic hyparlipidemic subjects at high cardiovascular risk[J].Artheroscler T hrombo Vase Biol,2003,23:7-16.
[9]沈诚,范士志,陈建明,李志平,等.抑制JAK/STAT通路对缺血再灌注损伤心肌TNF-α和IL-6表达的影响.重庆医学,2006,35(1):38-39.
[10]司良毅,陈运贞.缺血再灌注心肌白介素—2表达和N—乙酞半胱氨酸对损伤 影响的观察[J]第三军医大学学报,2002,24(5):581-584.
[11]ShibataM,E ndoS,In adaK,et al.El evated plasma levels of IL-1 receptor antagonist andI L-10 in patients with acute myocardial infarction[J].Interferon Cytokine Res,1997,17(3):145-148.
[12]李拥军,丁文惠,高炜,等.白介素-1受体拮抗剂对缺血再灌注心肌的保护作用及其机制探讨[J]。中华医学杂志,2004,84(7):548-553.
[13]Merchant SH,Gurule DM,Larson RS,et al.Amelioration of ischemia-reperfusion injury with cyclic peptide bloCPKade of ICAM-1[J].AmJ P hysiolH eartC ircP hysiol,2003,284(4):1260-1268.
[14]Yang XP,Irani K,Mattagajasingh S,et al.Signal Transducer and Activator of Transcription 3 {alpha 1 and Specificity Protein 1 Interact to Upregulate Intercelular Adhesion Molecule-1 in Ischemic-Reperfused Myocardium and Vascular Endothelium[J].Arterioscler Thromb Vasc Biol,2005,28(3);1-3
[15]沈诚,范士志,陈建明,等,中国体外循环杂志,2006,4(1):41-43.
[16]吴付轩,丁文惠,张钧华,等.急性心肌缺血再灌注期间血浆白介素-8的变化和意义[J].中国实用内科杂志,1999,19(9):527-529.
[17]张艳芳,杨廷桐,白细胞介素—1,8,10与心肌缺血一再灌注损伤[J].新乡医学院学报,2006,23(2):210-212.
[18]Krizanac-Bengez L,Kapural M,Parkinson F,et al.Effects of transient loss of shear stress on blood-brain barrier endothelium:role of nitric oxide and IL-6[J].Brain Res,2003,977(2):239-246.
[19]Smith EF 3rd,Egan JW,Bugelski PJ,et al.Temporal relation between neutrophil accumulation and myocardial reperfusion injury,Am J Physiol.1988 Nov;255(5 Pt 2):H1060-1068.
[20]Williams FM,Kus M,Tanda K,et al.Effect of duration of ischaemia on reduction of myocardial infarct size by inhibition of neutrophil accumulation using an anti-CD18 monoclonal antibody.Br J Pharmacol.1994;111(4):1123-1128.
[21]Klimas R,Siminiak T,WysoCPKi H,Neutrophil adherence-augmenting and chemotactic plasma activities in acute myocardial infarction: effect of fibrinolytic treatment, Int J Cardiol. 1993 Dec 31;42(3):239-244.
[22] Bell D, JaCPKson M, Nicoll JJ, et al. Inflammatory response, neutrophil activation, and free radical production after acute myocardial infarction: effect of thrombolytic treatment, Br Heart J. 1990 Feb;63(2):82-87.
[23] Niessen HW, Lagrand WK, Visser CA,,et al. Upregulation of ICAM-1 on cardiomyocytes in jeopardized human myocardium during infarction. Cardiovasc Res. 1999 Mar;41(3):603-610.
[24] Fein AM, Grant MM, Niederman MS, et al. Neutrophil-endothelial cell interaction in critical illness. Chest. 1991 Jun;99(6):1456-1462.
[25] Jones SP, Trocha SD, Strange MB, et al,Tumor necrosis factor mediates E-selectin production of the human heart[J]. Ann Thorac Surg, 2001,71(1):226-232.
[26] Dewald.O, Frangogiannis NG,, Zoerlein MP,,et al. A murine model of ischemic cardiomyopathy induced by repetitive ischemia and reperfusion Thorac Cardiovasc Surg. 2004 Oct;52(5):305-311.
[27] Fishbein MC, Maclean D, Maroko PR, et al. Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution, Am J Pathol. 1978;90(1):57-70.
[28] Romson JL, Hook BG, Kunkel SL,et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation.1983;67(5):1016-1023.
[29] Silver MJ, Sutton JM,, Hook S, et al. Adjunctive selectin bloCPKade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model. Circulation. 1995 ;92(3):492-499.
[30] Frangogiannis NG, Targeting the Inflammatory Response in Healing Myocardial Infarcts[J]. Current Medicinal Chemistry, 2006, 13, 1877-1893.
[31] Frangogiannis NG, Dewald O, Xia Y, et al. Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy, Circulation. 2007 Feb 6;115(5):584-592.
[32] Lahat N, Rabat MA, Ballan M, et al. Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-alpha secretion[ J].J Leukoc Biol,2003,74(2): 197-205.
[33] Kajihara N , Morita S , Nishida T, et al. Transfection with a dominant-negative inhibitor of monocyte chemoattractant protein-1 gene improves cardiac function after 6 hours of cold preservation[J] .Circulation, 2003 ,108 (Suppl 1):213-218.
[34] NakamuraT , Abu-Dahab R, Menger MD, et al. Depletion of alveolar macrophages by clodronate-liposomes aggravates ischemia-reperfusionin jury of the lung[J] J Heart Lung Transplant, 2005,24(1): 38-45.
[35] DaCosta ML, Yao Z, MacPherson BC, et al. Brief hypoxia conditionsm onocytesto p rotectre perfusedc ardiocytesag ainstce llde ath via the CDllb receptor[J].J Heart Lung Transplant, 2003, 22(9) ;979-985.
[36] Ito H, Nakano A, Kinoshita M, et al.Pioglitazone, a peroxiaome proliferator receptor-gamma agonist, attenuates myocardial ischemia/reperfusion injury in a rat model[J]. Lab Invest, 2003,83(12):1715-1720.
[37] Yue TL,Chen J, Bao W, et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone[J]. Circulation, 2001,104(21):2588-2590.
[38] Bhattacharya K, Farwell K, Huang M, Mast cell deficient W/Wv mice have lower serum IL-6 and less cardiac tissue necrosis than their normal littermates following myocardial ischemia-reperfusionlnt J Immunopathol Pharmacol. 2007 Jan-Mar;20(l):69-74.
[39] LiuYH, YangXP, MehtaD, et al. Role of kininsin chronic heart failure and in the therapeutic effect of ACE inhibitorsin kininogen-deficient rats[J]. Am J Physiol Heart Circ Physiol, 2000,278(2): H507-H514.
[40] Lazar HL, Bao Y, Rivers S, et al. Pretreatment with angiotensin converting enzyme inhibitors attenuates ischemia-reperfusion injury[J]. Ann Thorac Surg, 2002,73(5):1522-1527.
[41]Wang LX,Ideishi M,Yahiro E,et al.Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia reperfusion induced myocardial injury[J].Hypertens Res,2001,24(2):179-187.
[42]Kumari R,Maulik M,Manchanda SC,et al;Protective effect of bradykin in antagonist Hoe-140 during in vivo mycocardial ischemic-reperfusion injury in the cat[J].Regul Pept.2003,115(3):211-218.
[43]崔少波,赵学森,崔涛,等,缓激肽在苯那普利抗大鼠心肌缺血再灌注损伤中的作用,中国误诊学杂志 2006,16(8):1428-1430.
[44]Chun-Yang Xiao,Akiyoshi Hara,Koh-ichi Yuhki,Ischemia-Reperfusion Injury:A Study Using Mice LaCPKing Their Respective Roles of Prostaglandin I2 and Thromboxane A2 in Cardiac Receptors.Circulation 2001;104;2210-2215.
[45]Calabresi L,Rossoni G,Gomaraschi M,et al.High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-α content and enhancing prostaglandin release[J].Circ Res.2003;92:330-337.
[46]Chun-Yang Xiao,Koh-ichi Yuhki,Akiyoshi Hara,et al.Prostaglandin E2 Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP 4[J].Circulation 2004;109;2462-2468.
[47]Boli R,Shinmura K,Tang XL,et al,Discovery of a new function of cycloxygenase(COX-2):COX-2 is a cardiopretective protein in that aleviates ischemial/reperfusion injury and mediate the late phase of preconditioning[J].Cardiovasc Res,2002,55(3):506-519.
[48]Saito T,Rodger IW,Hu F,et al.Inhibition of cyclooxygenase-2 imoproves cardiac function in myocardiac infarction.[J].Biochem Biophys Res Commun,2000,273(2):772-775.
[49]Scheurenn N,Jochbs M,Ertl G,et al,Cyclooxygenase-2 in myocardiam stimulation by angiotensin-Ⅱ in cultured fibroblasts and role acute mvocardial infarction.[J] J Mol Cell Cardiol, 2002,34(l):29-37.
[50] Saito T, Rodger IW, Hu F, et al, Inhibition of COX pathway in experimental myocardial infarction [J]. J Mol Cell Cardiol, 2004,37(1):71-77.
[51] O'Shea, J.J. et al. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell, 2002,109 (Suppl), S121-S131.
[52] Levy, D.E, Darnell, J.E., Jr .Stats: transcriptional control and biological impact. Nat.Rev. Mol. Cell Biol. 2002,3: 651-662.
[53] Negoro, S. et al. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc. Res. 2002,47:797-805.
[54] Kunisada, K. et al. Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy. Proc. Natl. Acad. Sci. 2000,97:315-319.
[55] Negoro, S. et al. Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenationinduced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 2001,104:979-981.
[56] Oshima, Y. et al. STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc. Res. 2005, 65:428-435
[57] Hilfiker-Kleiner, D. et al. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition,and heart protection from ischemic injury. Circ. Res. 2004,95:187-195.
[58] Stephanou, A. et al. Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J. Biol. Chem. 2000,275:10002-10008.
[59] McCormiCPK, J. et al. Free radical scavenging inhibits STAT phosphorylation following in vivo ischemia/reperfusion injury. FASEB J. 2006,20:2115-2117.
[60] Xuan, Y.T. et al. Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J. Mol. Cell. Cardiol. 2003, 35:525-537.
[61] Xuan, Y.T. et al. An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc. Natl. Acad. Sci. 2001, 98:9050-9055.
[62] Hernandez Gutierrez S, Rojas del Castillo E. Role of the transcription factor NF-kappaB in the cardiac cell. Arch Cardiol Mex. 2005 Jul-Sep;75(3):363-370.
[63] Tillmanns J, Carlsen H, Blomhoff R, et al. Caught in the act: in vivo molecular imaging of the transcription factor NF-kappaB after myocardial infarction. Biochem Biophys Res Commun. 2006 Apr 14;342(3):773-774.
[64] Lu L, Chen SS, Zhang JQ, et al. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun. 2004 Sep 3;321(4):879-885.
[65] Kawamura N, Kubota T, Kawano S, et al, BloCPKade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy. Cardiovasc Res. 2005 ;66(3):520-529.
[66] Kawano S, Kubota T, Monden Y, et al, BloCPKade of NF-kappaB improves cardiac function and survival after myocardial infarction. Am J Physiol Heart Circ Physiol. 2006 Sep;291(3):H1337-344.