阿托伐他汀对正常/模拟缺血/再灌注心室肌快钠电流影响的系列研究
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摘要
背景：
缺血/再灌注性心律失常是影响急性冠脉综合征患者预后的重要事件,阿托伐他汀拥有的大量临床证据显示可以改善急性冠脉综合征患者的临床预后,亦包括减少心律失常的发生。但缺血/再灌注发生时心室肌快钠电流(IN。)发生怎样的变化,阿托伐他汀是否影响这些变化,且是通过怎样的途径影响这些变化,阿托伐他汀是否具有直接抑制细胞膜离子电流的作用,是否具有通过细胞内信号通路影响基因/蛋白的表达从而影响离子电流的作用,均为未知领域。
目的：
1.观察阿托伐他汀对大鼠正常和模拟缺血心室肌IN。的短时效应。2.观察大鼠心室肌INa在模拟缺血状态下变化的时间依赖性和阿托伐他汀对这一过程的影响。
3.观察模拟缺血/再灌注状态下大鼠心室肌INa的变化和阿托伐他汀对此过程的影响。4.观察再灌注损伤补救酶(Reperfusion Injury Salvage Kinase,RISK)信号通路核心蛋白磷酸化磷脂酰肌醇激酶(PI3K)抑制剂渥曼青霉素对模拟缺血/再灌注左室心室肌细胞INa的影响。5.观察模拟缺血/再灌注状态钠通道α亚单位SCN5A的变化。
方法：
应用Landgendorff逆灌流系统酶解分离左室心肌细胞。采用全细胞膜片钳技术观察大鼠左室心肌细胞INa。在系列研究不同阶段,通过改变电极外液的方法来模拟正常/模拟缺血/再灌注等细胞状态。分组对照研究分别观察阿托伐他汀对正常/模拟缺血/再灌注INa的影响,并在模拟缺血/再灌注各组加入RISK信号通路核心蛋白P13K的抑制剂：渥曼青霉素,观察阿托伐他汀的作用途径是否与RISK信号通路有关。采用分子生物学western blot技术观察心室肌细胞在模拟缺血/再灌注等不同状态下钠通道α亚单位SCN5A的表达水平。以SPSS统计软件分析数据,以P<0.05为差异有统计学意义。
结果：
1.应用阿托伐他汀短时作用3～5min正常和模拟缺血的标准化IN。峰值降低约25%(P<0.01),洗脱后电流基本恢复至基线水平(P>0.05),8.575mmol/L乙醇对标准化INa峰值无影响(P>0.05)。2.与基线比,缺血3min时INa增至1.15+0.08(P<0.01)并达峰,9min和11min时分别降至0.98±0.12和0.92+0.12(均P>0.05),至21main时减至0.56±0.13(P<0.01)；他汀组在缺血3mmin时和基线状态比无差别(分别为0.92±0.12和0.974±0.04,P>0.05),在15～17min其标准化IN。峰值变化曲线与单纯模拟缺血组有交叉。3.与缺血组相比,再灌注组和再灌注他汀组再灌注期间标准化IN。峰值均减小,V1/2增大(均P<0.05)；与再灌注组相比,再灌注他汀组标准化IN。峰值升高、k减小(均P<0.05)。即再灌注他汀组使IN。减小程度变小。4.在模拟缺血状态下渥曼青霉素组与单纯缺血组标准化INa峰值无差异(P>0.05)。渥曼青霉素阿托伐他汀组与单纯缺血组标准化IN。峰值无差异(P>0.05),但与缺血他汀组有差异(P<0.05)。在模拟再灌注状态下,标准化IN。峰值在再灌注他汀组和再灌注渥曼青霉素组均显示大于再灌注组(均P<0.05),而均小于持续缺血组(均P<0.05)。但再灌注他汀渥曼青霉素组未显示与再灌注组差异(P>0.05)。SCN5A的变化与INa的变化相符。
结论：
1.阿托伐他汀对正常和模拟缺血的大鼠心室肌细胞IN。短时作用(3～5min)类似于钠通道阻滞剂。2.大鼠心室肌细胞INa在模拟缺血状态下的变化具有时间依赖性,呈先增大后减小过程。3.在模拟再灌流状态下大鼠心室肌细胞INa较模拟缺血状态下的INa进一步减小,提示缺血再灌注损伤抑制INa。4.阿托伐他汀可使长时间(15min以后)模拟缺血或模拟缺血/再灌注损伤所致大鼠心室肌细胞INa减小程度变小,提示阿托伐他汀具有针对缺血再灌注损伤的保护作用。5.在模拟缺血和再灌注状态下,阿托伐他汀效应均可被渥曼青霉素部分抵消,提示阿托伐他汀可以通过RISK信号通路中的核心蛋白PI3K影响SCN5A的表达和IN。水平,并发挥针对缺血再灌注的保护作用。总体而言,阿托伐他汀有类似钠通道阻滞剂的作用,亦具有通过细胞内信号通路影响钠通道蛋白表达水平的作用,其对IN。的影响是多方面的。
Background:Ischemia/reperfusion related arrhythmia is one of important complications of acute coronary syndrom and may affect the prognosis. Some clinical trials have shown that statins have anti-arrhythmic effects and can improve clinical outcomes. But its mechanism is still unclear.
Objectives:1.To observe the short-time effects of atorvastatin on transient sodium currents (INa) of normal cell and the simulated ischemic cell in rat left ventricle;2.To observe time dependent effects of simulated ischemia on INa of rat left ventricular myocytes, and the effects of atorvastatin on ischemia INa;3.To observe the effects of atorvastatin on INa of rat simulated ischemia/reperfusion ventricular cells;4.To observe the effect of the core protein of RISK signal pathway:PI3K inhibitor on INa of rat simulated ischemia/reperfusion ventricular cells and its relationship with atorvastatin;5.To observe changes of SCN5A in status of normal cell and the simulated ischemia/reperfusion cell in rat left ventricle.
Methods:Ventricular cells were enzymatically isolated by Langendorff perfusion system. INa was recorded by using whole-cell patch clamp method. Some elements of extracellular fluid were hanged to simulate the status of normal, ischemia and reperfusion condition. Then the effects of atorvastatin and wortmannin on INa were observed.The expression level of SCN5A of simulated ventricular ischemia/reperfusion cell was measured by western blot technique.
Results:1. The short-time(3-5min) effects of atorvastatin on the rat normal and simulated ischemia ventricular peak INa were inhibited about25%(P<0.05), and after elution, the effect of inhibition was disappear.2. In simulated ischemia status, INa reached to the peak in3min at1.15±0.08(P<0.01), then decreased gradually; in the application of atorvastatin,INa inhibited the INa increasing progress at3min, however,15min after simulated ischemia which inhibited the INa decreasing progress.3. In simulated reperfusion status, INa reduced and atorvastatin inhibited the reduction degree.4. Wortmannin itself had no effect of INa in the status of simulated ischemia (P>0.05). INa in the atorvastatin and wortmannin combination group was higher than which in the group of atorvastatin (P<0.05), but had no difference with ischemia group (P>0.05). In the status of simulated reperfusion, the INa results of atorvastatin group and wortmannin group were higer than which of reperfusion group (P<0.05) and lower than which of persistant ischemia group (P<0.05), while INa of the atorvastatin and wortmannin combination group had no difference with which of reperfusion group (P>0.05). The expression level of SCN5A had the almost same changes with INa
Conclusions:1.The short time (3-5min) effect of Atorvastatin in INa of the normal and simulated ischemia rat ventricular myocytes is inhibition, similar to sodium channel blockers.2.The effects of simulated ischemia on INa are time dependent, firstly increase then decrease.3.In the status of reperfusion, INa decreases more than which in the status of ischemia.4.Atorvastatin can protect the decrease of INa in the status of simulated long-time(>15mins) ischemia/reperfusion.5. Wortmannin itself has no effect of INa in the status of simulated ischemia.6.Effects of Atorvastatin in the status of simulated ischemic/reperfusion can be partly overcomed by Wortmannin, which means atorvastatin can affect INa and the expression level of SCN5A through the way of RISK signal pathway especially of PI3K.7.Overall, atorvastatin can affect INa of the normal, simulated ischemic/reperfusion cell in rat left ventricle not only by blocking sodium channel directely but also by affecting the genes and proteins expression.
缺血/再灌注性心律失常是影响急性冠脉综合征患者预后的重要事件,阿托伐他汀拥有的大量临床证据显示可以改善急性冠脉综合征患者的临床预后,亦包括减少心律失常的发生。但缺血/再灌注发生时心室肌快钠电流(IN。)发生怎样的变化,阿托伐他汀是否影响这些变化,且是通过怎样的途径影响这些变化,阿托伐他汀是否具有直接抑制细胞膜离子电流的作用,是否具有通过细胞内信号通路影响基因/蛋白的表达从而影响离子电流的作用,均为未知领域。
目的：
1.观察阿托伐他汀对大鼠正常和模拟缺血心室肌IN。的短时效应。2.观察大鼠心室肌INa在模拟缺血状态下变化的时间依赖性和阿托伐他汀对这一过程的影响。
3.观察模拟缺血/再灌注状态下大鼠心室肌INa的变化和阿托伐他汀对此过程的影响。4.观察再灌注损伤补救酶(Reperfusion Injury Salvage Kinase,RISK)信号通路核心蛋白磷酸化磷脂酰肌醇激酶(PI3K)抑制剂渥曼青霉素对模拟缺血/再灌注左室心室肌细胞INa的影响。5.观察模拟缺血/再灌注状态钠通道α亚单位SCN5A的变化。
方法：
应用Landgendorff逆灌流系统酶解分离左室心肌细胞。采用全细胞膜片钳技术观察大鼠左室心肌细胞INa。在系列研究不同阶段,通过改变电极外液的方法来模拟正常/模拟缺血/再灌注等细胞状态。分组对照研究分别观察阿托伐他汀对正常/模拟缺血/再灌注INa的影响,并在模拟缺血/再灌注各组加入RISK信号通路核心蛋白P13K的抑制剂：渥曼青霉素,观察阿托伐他汀的作用途径是否与RISK信号通路有关。采用分子生物学western blot技术观察心室肌细胞在模拟缺血/再灌注等不同状态下钠通道α亚单位SCN5A的表达水平。以SPSS统计软件分析数据,以P<0.05为差异有统计学意义。
结果：
1.应用阿托伐他汀短时作用3～5min正常和模拟缺血的标准化IN。峰值降低约25%(P<0.01),洗脱后电流基本恢复至基线水平(P>0.05),8.575mmol/L乙醇对标准化INa峰值无影响(P>0.05)。2.与基线比,缺血3min时INa增至1.15+0.08(P<0.01)并达峰,9min和11min时分别降至0.98±0.12和0.92+0.12(均P>0.05),至21main时减至0.56±0.13(P<0.01)；他汀组在缺血3mmin时和基线状态比无差别(分别为0.92±0.12和0.974±0.04,P>0.05),在15～17min其标准化IN。峰值变化曲线与单纯模拟缺血组有交叉。3.与缺血组相比,再灌注组和再灌注他汀组再灌注期间标准化IN。峰值均减小,V1/2增大(均P<0.05)；与再灌注组相比,再灌注他汀组标准化IN。峰值升高、k减小(均P<0.05)。即再灌注他汀组使IN。减小程度变小。4.在模拟缺血状态下渥曼青霉素组与单纯缺血组标准化INa峰值无差异(P>0.05)。渥曼青霉素阿托伐他汀组与单纯缺血组标准化IN。峰值无差异(P>0.05),但与缺血他汀组有差异(P<0.05)。在模拟再灌注状态下,标准化IN。峰值在再灌注他汀组和再灌注渥曼青霉素组均显示大于再灌注组(均P<0.05),而均小于持续缺血组(均P<0.05)。但再灌注他汀渥曼青霉素组未显示与再灌注组差异(P>0.05)。SCN5A的变化与INa的变化相符。
结论：
1.阿托伐他汀对正常和模拟缺血的大鼠心室肌细胞IN。短时作用(3～5min)类似于钠通道阻滞剂。2.大鼠心室肌细胞INa在模拟缺血状态下的变化具有时间依赖性,呈先增大后减小过程。3.在模拟再灌流状态下大鼠心室肌细胞INa较模拟缺血状态下的INa进一步减小,提示缺血再灌注损伤抑制INa。4.阿托伐他汀可使长时间(15min以后)模拟缺血或模拟缺血/再灌注损伤所致大鼠心室肌细胞INa减小程度变小,提示阿托伐他汀具有针对缺血再灌注损伤的保护作用。5.在模拟缺血和再灌注状态下,阿托伐他汀效应均可被渥曼青霉素部分抵消,提示阿托伐他汀可以通过RISK信号通路中的核心蛋白PI3K影响SCN5A的表达和IN。水平,并发挥针对缺血再灌注的保护作用。总体而言,阿托伐他汀有类似钠通道阻滞剂的作用,亦具有通过细胞内信号通路影响钠通道蛋白表达水平的作用,其对IN。的影响是多方面的。
Background:Ischemia/reperfusion related arrhythmia is one of important complications of acute coronary syndrom and may affect the prognosis. Some clinical trials have shown that statins have anti-arrhythmic effects and can improve clinical outcomes. But its mechanism is still unclear.
Objectives:1.To observe the short-time effects of atorvastatin on transient sodium currents (INa) of normal cell and the simulated ischemic cell in rat left ventricle;2.To observe time dependent effects of simulated ischemia on INa of rat left ventricular myocytes, and the effects of atorvastatin on ischemia INa;3.To observe the effects of atorvastatin on INa of rat simulated ischemia/reperfusion ventricular cells;4.To observe the effect of the core protein of RISK signal pathway:PI3K inhibitor on INa of rat simulated ischemia/reperfusion ventricular cells and its relationship with atorvastatin;5.To observe changes of SCN5A in status of normal cell and the simulated ischemia/reperfusion cell in rat left ventricle.
Methods:Ventricular cells were enzymatically isolated by Langendorff perfusion system. INa was recorded by using whole-cell patch clamp method. Some elements of extracellular fluid were hanged to simulate the status of normal, ischemia and reperfusion condition. Then the effects of atorvastatin and wortmannin on INa were observed.The expression level of SCN5A of simulated ventricular ischemia/reperfusion cell was measured by western blot technique.
Results:1. The short-time(3-5min) effects of atorvastatin on the rat normal and simulated ischemia ventricular peak INa were inhibited about25%(P<0.05), and after elution, the effect of inhibition was disappear.2. In simulated ischemia status, INa reached to the peak in3min at1.15±0.08(P<0.01), then decreased gradually; in the application of atorvastatin,INa inhibited the INa increasing progress at3min, however,15min after simulated ischemia which inhibited the INa decreasing progress.3. In simulated reperfusion status, INa reduced and atorvastatin inhibited the reduction degree.4. Wortmannin itself had no effect of INa in the status of simulated ischemia (P>0.05). INa in the atorvastatin and wortmannin combination group was higher than which in the group of atorvastatin (P<0.05), but had no difference with ischemia group (P>0.05). In the status of simulated reperfusion, the INa results of atorvastatin group and wortmannin group were higer than which of reperfusion group (P<0.05) and lower than which of persistant ischemia group (P<0.05), while INa of the atorvastatin and wortmannin combination group had no difference with which of reperfusion group (P>0.05). The expression level of SCN5A had the almost same changes with INa
Conclusions:1.The short time (3-5min) effect of Atorvastatin in INa of the normal and simulated ischemia rat ventricular myocytes is inhibition, similar to sodium channel blockers.2.The effects of simulated ischemia on INa are time dependent, firstly increase then decrease.3.In the status of reperfusion, INa decreases more than which in the status of ischemia.4.Atorvastatin can protect the decrease of INa in the status of simulated long-time(>15mins) ischemia/reperfusion.5. Wortmannin itself has no effect of INa in the status of simulated ischemia.6.Effects of Atorvastatin in the status of simulated ischemic/reperfusion can be partly overcomed by Wortmannin, which means atorvastatin can affect INa and the expression level of SCN5A through the way of RISK signal pathway especially of PI3K.7.Overall, atorvastatin can affect INa of the normal, simulated ischemic/reperfusion cell in rat left ventricle not only by blocking sodium channel directely but also by affecting the genes and proteins expression.
引文
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