延迟相缺血预处理和缺血后处理对心脏缺血再灌注损伤保护作用的实验研究
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摘要
[目的]为研究缺血预适应机制,评价心肌缺血再灌注损伤药物疗效等相关研究提供理想的实验模型。
[方法]共30只雄性C57BL／6小鼠,其中20只用于建立缺血再灌注损伤模型,10只作为假手术组。C57BL／6麻醉开胸后,用7／0医用单丝线穿过心脏冠状动脉左前降支(LAD)下方,结扎LAD 30分钟后,剪开缝线,关闭胸腔,待小鼠苏醒后撤离呼吸机。
[结果]行30分钟LAD结扎术后再灌注模型组存活率为19／20；假手术组存活率为10／10。经过氯化三苯四氮唑(TTC)和伊文思蓝染色,测量30分钟I/R实验组中缺血危险区为59.5±0.9%,假手术组缺血危险区为60.7±1.1%；30分钟I/R实验组梗死面积为32.2±0.7%,假手术组无心肌无梗死形成
[结论]采用本方法制作小鼠心肌缺血／再灌注损伤模型成功率高,且操作简单,创伤小
[目的]心肌缺血预处理根据对缺血心肌起保护作用的时间分为缺血预处理的早期相和延迟相。近年来,大量的研究表明缺血预处理延迟相出现在缺血预处理后24小时,对心脏保护持续时间长,保护范围广。但是缺血预处理延迟相对心肌组织中的氧分压的影响和其作用机制尚不清楚。因此,我们通过建立小鼠缺血再灌注损伤模型,研究缺血预处理延迟相是否通过降低再灌注后心肌组织中氧分压水平保护线粒体功能减轻氧化应激损伤,从而减少梗死面积的形成。
[方法]小鼠随机分为假手术组,单纯缺血预处理组(5分钟缺血／5分钟再灌,共3个循环,LPC),单纯缺血再灌注组(30分钟缺血后再灌60分钟或24小时,I/R)和缺血预处理延迟相组(LPC+I/R).心肌组织中的氧分压通过电子顺磁共振(EPR)测量,局部血流量通过激光多普勒方式测量,线粒体活性通过电子传递链复合酶活性反映,心肌梗死面积通过TTC和伊凡思蓝双染色进行定量。
[结果]在I／R实验组中,再灌注后心肌组织中的氧分压升高,较之缺血前水平显著升高,通过缺血预处理后LPC+I/R实验组中小鼠心肌组织中的氧分压水平较I／R组降低；与假手术相比较复合酶Ⅱ和复合酶Ⅲ(琥珀酸细胞色素c还原酶,SCR),细胞色素c氧化酶(CcO)以及还原型烟酰胺腺嘌呤二核苷酸脱氢酶(NADH-DH)在LPC组中均升高,但在I／R实验组中活性均降低,通过缺血预处理后LPC+I/R实验组SCR, CcO和NADH-DH活性与假手术组无明显改变；锰超氧化物歧化酶在LPC实验组和LPC+I/R实验组中增加。
[结论]研究结果表明延迟相缺血预处理可能通过增加锰超氧化物歧化酶的表达维持了SCR, CcO以及NADH-DN的活性,保护了线粒体的功能,有效减轻缺血后高氧合状态,减轻了缺血再灌损伤。
[目的]长时间缺血后充分再灌注前通过短时多次的缺血／在灌注过程可有效降低缺血再灌注损伤,即缺血后处理(IPOC)。缺血梗死的严重程度与缺血时间成正相关,研究表明当缺血时间过短或者过长都会影响IPOC的保护效果。因此我们研究目的旨在揭示不同缺血时间条件下,缺血后处理对对缺血再灌注损伤的影响,从而确定缺血后处理对缺血后心脏保护作用的“窗口期”,并阐明其发生机制。
[方法]野生型C57BL／6小鼠随机分为15,30,45和60分钟缺血再灌注实验组,和15,30,45,60分钟缺血后处理组及假手术组。体内组织氧分压采用电子顺磁共振法测量。局部血流量采用激光多普勒技术测定。再灌后60分钟缺血危险区心肌组织标本用于测定线粒体酶(琥珀酸细胞色素c还原酶,还原型烟酰胺腺嘌呤二核苷酸脱氢酶以及细胞色素C氧化酶)活性。再灌后24小时心脏用于测定梗死面积。
[结果]缺血后梗死面积的测量表明：15分钟缺血时在I/R组和IPOC组中均无梗死形成。与I/R组想比较IPOC可有效保护30分钟(12.4±2.2 vs.32.2±0.7%)和45分钟(21.0±1.3 vs.37.9±0.7%)缺血心脏,但对60分钟缺血后心脏无保护作用(46.44±2.9 vs.45.6±3.8%)。缺血后处理可显著降低30分钟和45分钟缺血后再灌注心肌组织中氧分压,但对60分钟长时间缺血时无明显改善。局部血流量测定显示在30分钟,45分钟和60分钟缺血实验中,再灌注60分钟时局部血流量逐渐降,分别是5.3±0.4,4.3±0.1和3.9±0.2(a.u.)。缺血后处理可以显著改善30分钟和45分钟局部血流量(7.2±0.2,5.2±0.3)。缺血后处理对30分钟和45分钟缺血时心肌组织线粒体酶活性具有保护作用,但对60分钟实验组无影响。
[结论]缺血后处理对缺血再灌注损伤心脏的保护作用具有“窗口期”效应。对缺血30分钟和45分钟再灌心脏具有明显的保护作用。主要通过提高局部血流量和维持线粒体功能完成。
Objective To improve the procedure of establishing animal model of myocardial ischemia and reperfusion (I/R) in mice.
Methods Male C57BL/6 mice were anethetized, the chest was opened with a mouse respirator, a 7/0 silk suture was placed around the left anterior descending coronary artery (LAD), a polyethylene tube (PE) was placed under the silk suture. The LAD was ligated for 30 min, reperfusion was achieved by releasing the tension applied to ligature for 24 h.
Result A total of 20 C57BL/6 were allocated into I/R group and shame control group. The survival rate in 30-min I/R group is 9/10 after 24 h reperfusion and the infarct area is 32.2±0.7% and the AAR (total left ventricle (LV) area-non-ischemic area) over the area of left ventricle is 59.5±0.9%. Conclusions A repeatable and simple technique for mouse model of myocardial ischemia and reperfusion injury can be established.
Objective The late phase ischemic preconditioning (24 hours later) strongly protects against ischemia reperfusion injury. However, its effect on myocardial oxygenation and related mechanism(s) are unknown. Therefore, we determine in an in vivo mouse model of regional ischemia and reperfusion (I/R) whether late phase preconditioning attenuates post-ischemic myocardial hyperoxygenation with preservation of mitochondrial function.
Methods Four groups of mice were studied:sham, late phase preconditioning (LPC,3 cycles of 5 min coronary occlusion/5 min reperfusion), ischemia reperfusion (I/R,30 min ischemia followed by 60 min reperfusion), and LPC+I/R mice.
Results Tissue Po2 upon reperfusion rose significantly above the pre-ischemic value in the I/R mice. This hyperoxygenation status was attenuated in the PC+I/R mice. Activities of complexⅡandⅢ(SCR) and cytochrome c oxidase (CcO) were increased in the PC group, reduced in the I/R group, but conserved in the PC+I/R group compared with sham control. The activity of NADH dehydrogenase (NADH-DH) showed no significant difference between sham and the PC group, but was reduced in the I/R group and recovered in the PC+I/R group. The expression of Mn-SOD was increased in the PC and PC+I/R group compared with sham control.
Conclusion Taken together, these data suggest that the late phase PC attenuates post-ischemic myocardial hyperoxygenation and preserves mitochondrial O2 metabolism due to increased SCR and CcO activities and conserved NADH-DH activity and increased Mn-SOD expression.
Objective Ischemic post-conditioning (IPOC) is a powerful method to reduce ischemia and reperfusion injury. Studies also demonstrate that IPOC could be deleterious when the ischemia duration was either too short or too long. Our study is to determine whether there is a salvageable ischemic time window for IPOC and the potential mechanisms involved.
Methods C57BL/6 mice underwent 30,45 and 60 min left anterior descending coronary artery (LAD) occlusion followed by reperfusion, w/o IPOC. In vivo tissue oxygenation was monitored with electron paramagnetic resonance (EPR) oximetry. Regional Blood Flow (RBF) was measured by the laser Doppler perfusion monitor. Tissue from the risk area was collected and the activities of mitochondrial were assayed.
Results The tissue oximetry data demonstrated that IPOC attenuated tissue hyperoxygenation with 45 but not 30 and 60 min ischemia. IPOC improved the RBF with 30 and 45 but not 60 min ischemia. IPOC preserved the activities of mitochondrial enzymes activities at 30 and 45 but not 60 min ischemia. Infarct size measurement indicated that IPOC protected the heart with 30 min and 45 min but not 60 min ischemia.
Conclusions The cardioprotection afforded by IPOC is limited to a time window between 30 and 45 min LAD occlusion in mouse. This salvageable ischemic time window is determined by the effect of IPOC on improving the RBF and mitochondrial function.
[方法]共30只雄性C57BL／6小鼠,其中20只用于建立缺血再灌注损伤模型,10只作为假手术组。C57BL／6麻醉开胸后,用7／0医用单丝线穿过心脏冠状动脉左前降支(LAD)下方,结扎LAD 30分钟后,剪开缝线,关闭胸腔,待小鼠苏醒后撤离呼吸机。
[结果]行30分钟LAD结扎术后再灌注模型组存活率为19／20；假手术组存活率为10／10。经过氯化三苯四氮唑(TTC)和伊文思蓝染色,测量30分钟I/R实验组中缺血危险区为59.5±0.9%,假手术组缺血危险区为60.7±1.1%；30分钟I/R实验组梗死面积为32.2±0.7%,假手术组无心肌无梗死形成
[结论]采用本方法制作小鼠心肌缺血／再灌注损伤模型成功率高,且操作简单,创伤小
[目的]心肌缺血预处理根据对缺血心肌起保护作用的时间分为缺血预处理的早期相和延迟相。近年来,大量的研究表明缺血预处理延迟相出现在缺血预处理后24小时,对心脏保护持续时间长,保护范围广。但是缺血预处理延迟相对心肌组织中的氧分压的影响和其作用机制尚不清楚。因此,我们通过建立小鼠缺血再灌注损伤模型,研究缺血预处理延迟相是否通过降低再灌注后心肌组织中氧分压水平保护线粒体功能减轻氧化应激损伤,从而减少梗死面积的形成。
[方法]小鼠随机分为假手术组,单纯缺血预处理组(5分钟缺血／5分钟再灌,共3个循环,LPC),单纯缺血再灌注组(30分钟缺血后再灌60分钟或24小时,I/R)和缺血预处理延迟相组(LPC+I/R).心肌组织中的氧分压通过电子顺磁共振(EPR)测量,局部血流量通过激光多普勒方式测量,线粒体活性通过电子传递链复合酶活性反映,心肌梗死面积通过TTC和伊凡思蓝双染色进行定量。
[结果]在I／R实验组中,再灌注后心肌组织中的氧分压升高,较之缺血前水平显著升高,通过缺血预处理后LPC+I/R实验组中小鼠心肌组织中的氧分压水平较I／R组降低；与假手术相比较复合酶Ⅱ和复合酶Ⅲ(琥珀酸细胞色素c还原酶,SCR),细胞色素c氧化酶(CcO)以及还原型烟酰胺腺嘌呤二核苷酸脱氢酶(NADH-DH)在LPC组中均升高,但在I／R实验组中活性均降低,通过缺血预处理后LPC+I/R实验组SCR, CcO和NADH-DH活性与假手术组无明显改变；锰超氧化物歧化酶在LPC实验组和LPC+I/R实验组中增加。
[结论]研究结果表明延迟相缺血预处理可能通过增加锰超氧化物歧化酶的表达维持了SCR, CcO以及NADH-DN的活性,保护了线粒体的功能,有效减轻缺血后高氧合状态,减轻了缺血再灌损伤。
[目的]长时间缺血后充分再灌注前通过短时多次的缺血／在灌注过程可有效降低缺血再灌注损伤,即缺血后处理(IPOC)。缺血梗死的严重程度与缺血时间成正相关,研究表明当缺血时间过短或者过长都会影响IPOC的保护效果。因此我们研究目的旨在揭示不同缺血时间条件下,缺血后处理对对缺血再灌注损伤的影响,从而确定缺血后处理对缺血后心脏保护作用的“窗口期”,并阐明其发生机制。
[方法]野生型C57BL／6小鼠随机分为15,30,45和60分钟缺血再灌注实验组,和15,30,45,60分钟缺血后处理组及假手术组。体内组织氧分压采用电子顺磁共振法测量。局部血流量采用激光多普勒技术测定。再灌后60分钟缺血危险区心肌组织标本用于测定线粒体酶(琥珀酸细胞色素c还原酶,还原型烟酰胺腺嘌呤二核苷酸脱氢酶以及细胞色素C氧化酶)活性。再灌后24小时心脏用于测定梗死面积。
[结果]缺血后梗死面积的测量表明：15分钟缺血时在I/R组和IPOC组中均无梗死形成。与I/R组想比较IPOC可有效保护30分钟(12.4±2.2 vs.32.2±0.7%)和45分钟(21.0±1.3 vs.37.9±0.7%)缺血心脏,但对60分钟缺血后心脏无保护作用(46.44±2.9 vs.45.6±3.8%)。缺血后处理可显著降低30分钟和45分钟缺血后再灌注心肌组织中氧分压,但对60分钟长时间缺血时无明显改善。局部血流量测定显示在30分钟,45分钟和60分钟缺血实验中,再灌注60分钟时局部血流量逐渐降,分别是5.3±0.4,4.3±0.1和3.9±0.2(a.u.)。缺血后处理可以显著改善30分钟和45分钟局部血流量(7.2±0.2,5.2±0.3)。缺血后处理对30分钟和45分钟缺血时心肌组织线粒体酶活性具有保护作用,但对60分钟实验组无影响。
[结论]缺血后处理对缺血再灌注损伤心脏的保护作用具有“窗口期”效应。对缺血30分钟和45分钟再灌心脏具有明显的保护作用。主要通过提高局部血流量和维持线粒体功能完成。
Objective To improve the procedure of establishing animal model of myocardial ischemia and reperfusion (I/R) in mice.
Methods Male C57BL/6 mice were anethetized, the chest was opened with a mouse respirator, a 7/0 silk suture was placed around the left anterior descending coronary artery (LAD), a polyethylene tube (PE) was placed under the silk suture. The LAD was ligated for 30 min, reperfusion was achieved by releasing the tension applied to ligature for 24 h.
Result A total of 20 C57BL/6 were allocated into I/R group and shame control group. The survival rate in 30-min I/R group is 9/10 after 24 h reperfusion and the infarct area is 32.2±0.7% and the AAR (total left ventricle (LV) area-non-ischemic area) over the area of left ventricle is 59.5±0.9%. Conclusions A repeatable and simple technique for mouse model of myocardial ischemia and reperfusion injury can be established.
Objective The late phase ischemic preconditioning (24 hours later) strongly protects against ischemia reperfusion injury. However, its effect on myocardial oxygenation and related mechanism(s) are unknown. Therefore, we determine in an in vivo mouse model of regional ischemia and reperfusion (I/R) whether late phase preconditioning attenuates post-ischemic myocardial hyperoxygenation with preservation of mitochondrial function.
Methods Four groups of mice were studied:sham, late phase preconditioning (LPC,3 cycles of 5 min coronary occlusion/5 min reperfusion), ischemia reperfusion (I/R,30 min ischemia followed by 60 min reperfusion), and LPC+I/R mice.
Results Tissue Po2 upon reperfusion rose significantly above the pre-ischemic value in the I/R mice. This hyperoxygenation status was attenuated in the PC+I/R mice. Activities of complexⅡandⅢ(SCR) and cytochrome c oxidase (CcO) were increased in the PC group, reduced in the I/R group, but conserved in the PC+I/R group compared with sham control. The activity of NADH dehydrogenase (NADH-DH) showed no significant difference between sham and the PC group, but was reduced in the I/R group and recovered in the PC+I/R group. The expression of Mn-SOD was increased in the PC and PC+I/R group compared with sham control.
Conclusion Taken together, these data suggest that the late phase PC attenuates post-ischemic myocardial hyperoxygenation and preserves mitochondrial O2 metabolism due to increased SCR and CcO activities and conserved NADH-DH activity and increased Mn-SOD expression.
Objective Ischemic post-conditioning (IPOC) is a powerful method to reduce ischemia and reperfusion injury. Studies also demonstrate that IPOC could be deleterious when the ischemia duration was either too short or too long. Our study is to determine whether there is a salvageable ischemic time window for IPOC and the potential mechanisms involved.
Methods C57BL/6 mice underwent 30,45 and 60 min left anterior descending coronary artery (LAD) occlusion followed by reperfusion, w/o IPOC. In vivo tissue oxygenation was monitored with electron paramagnetic resonance (EPR) oximetry. Regional Blood Flow (RBF) was measured by the laser Doppler perfusion monitor. Tissue from the risk area was collected and the activities of mitochondrial were assayed.
Results The tissue oximetry data demonstrated that IPOC attenuated tissue hyperoxygenation with 45 but not 30 and 60 min ischemia. IPOC improved the RBF with 30 and 45 but not 60 min ischemia. IPOC preserved the activities of mitochondrial enzymes activities at 30 and 45 but not 60 min ischemia. Infarct size measurement indicated that IPOC protected the heart with 30 min and 45 min but not 60 min ischemia.
Conclusions The cardioprotection afforded by IPOC is limited to a time window between 30 and 45 min LAD occlusion in mouse. This salvageable ischemic time window is determined by the effect of IPOC on improving the RBF and mitochondrial function.
引文
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