心肌缺血/再灌注损伤及钙调神经磷酸酶信号通路的调控作用
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摘要
心肌缺血再灌注(I/R)损伤可产生心肌细胞凋亡和坏死,导致心肌梗死面积扩大、心室重塑和心力衰竭。本研究从心肌I/R损伤致细胞凋亡的钙超载机制入手,探讨了钙调神经磷酸酶(CaN)抑制剂FK506在心肌I/R损伤过程中的作用,揭示了CaN在心肌I/R损伤致心肌细胞凋亡的调控机制。以大鼠H9c2心肌细胞为研究对象,采用四甲基偶氮唑盐(MTT)法检测过氧化氢对心肌细胞的损伤作用,单细胞凝胶电泳法检测DNA损伤,吖啶橙/溴乙锭(AO/EB)双荧光染色和流式细胞术检测细胞凋亡;并建立大鼠H9c2心肌细胞凋亡的损伤模型,给予不同剂量FK506,采用流式细胞术检测细胞凋亡率,观察FK506对心肌细胞凋亡的影响。建立大鼠心肌I/R损伤模型为研究对象,给予FK506进行干预,观察I/R损伤及药物干预后心肌梗死面积,心律失常程度以及血压的变化,采用生物化学法检测心肌细胞脂质过氧化水平、组织酶CK和LDH活性变化,采用免疫组织化学法检测心肌细胞凋亡相关蛋白的表达,采用Western Blot方法检测CaN蛋白的表达情况。结果表明:H2O2可引起心肌细胞的DNA损伤,诱导细胞凋亡。FK506对H2O2诱导的大鼠H9c2心肌细胞凋亡具有抑制作用。FK506干预可缩小心肌梗死面积,减轻心肌I/R损伤。FK506可增加Bcl-2蛋白表达,抑制心肌细胞凋亡。因此,FK506通过线粒体途径诱导心肌I/R损伤所致的心肌细胞凋亡,CaN在I/R损伤中具有重要作用。抑制CaN活性对于抑制心肌I/R损伤,减少心肌细胞凋亡,改善心脏功能具有特别重要的意义。
After an acute ischemic heart disease, early and successful myocardial reperfusion is an effictive strategy for obtaining thoroughly coronary blood flow, saving the dying myocardiocyte and reducing the size of a myocardial infarct. Because of the uncertainty relates to the ischemic period and degree, myocardial ischemia/reperfusion injury caused by the restoration of coroary blood flow after an ischemic episode. This form of myocardial injury can induce cardiomyocyte apoptosis and necrosis, increase infarct size, remodel cardiac ventricle, then the ultmate incidence is cardiac failure. To observe H_2O_2-induced myocardial H9c2 cell apoptosis and pretective effect of inhibitor of calcineurin (CaN), a cell apoptotic model from rat myocardiocytes cell line H9c2 induced by hydrogen dioxide (H_2O_2) and a rat model of ischemia/reperfusion are established. These provide theoretical basis for study on CaN induced myocardiocyte apoptosis caused by ischemia/reperfusion indury and related mechanism.
1.Toxicity of H_2O_2 on H9c2 cells
1.1 The survival rate of H9c2 cell detected by MTT MTT assay was performed to detect the toxicity after 1, 3, 6, 12 and 24 h exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L). It was showed the survival rate decreased with the increase of dosage and duration of exposure to H_2O_2. After 6 h exposure to 200μmol/L H_2O_2,half of the H9c2 cells died. The change of survival rate was over 60%, with 24 h after exposure 400μmol/L H_2O_2. There was significant difference in survival rate between H_2O_2 group and control group(NC) (P < 0.05). The results suggest that cardiomyocytes are sensitive to H_2O_2-induced dosage.
1.2 DNA damage of H9c2 cells
Single cell gel electrophoresis (SCGE) assay was used to examine DNA damage of H9c2 cells 6 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L). When exposed to 50, 100, 200 and 400μmol/L H_2O_2 for 6 h, there were significant difference from control group. The results suggest H_2O_2 could cause DNA damage of myocardiocytes in dose dependant way.
1.3 Apoptosis detected by AO/EB double fluorescent staining assay There were distinctive changes on cell apoptosis observed under fluorescence microscope 1, 3, 6 and 12 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L) by AO/EB double staining. The H9c2 cells occur obviously morphological changes in H_2O_2 -exposed groups, and the apoptotic rate was a significant increase compared with control group (P < 0.05), the highest group at 6 h after exposure to 100μmol/L H_2O_2. Whthin a prolong time exposure to it, the change of apoptotic rate is not obvious.
1.4 Apoptosis detected by FCM with AnnexinⅤ/PI double fluorescent staining Cell apoptosis was observed by FCM 1, 6 and 24 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L). The apoptotic rates were significantly increased in 100, 200 and 400μmol/L H_2O_2 at 6 and 24 h compared with control group(P < 0.05), the highest group at 24 h after exposure to 400μmol/L H_2O_2. The results suggest H_2O_2 could induce the H9c2 cell apoptosis in dose dependant and time dependant way.
1.5 Membrane potential detected by FCM with Rhodamine 123 fluorescent prode
Mitochondria membrane potential (Δψmt) was observed by FCM 1, 6 and 24 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L).Δψmt showed the significant increase in H_2O_2 -exposed groups at 1 h compared with control group (P < 0.05). Whthin a prolong time exposure to it, the change ofΔψmt is observed. Compared with control group,Δψmt showed the significant increase in 50 and 100μmol/L H_2O_2 at 6 h, and the significant decrease in 200 and 400μmol/L H_2O_2 at 24h (P < 0.05). The results suggest H_2O_2 could damage mitochondria, decreaseΔψmt and induce the apoptosis in myocardial H9c2 cell.
2. Effect of inhibitor of calcineurin on myocardial H9c2 cell apoptosis induced by H_2O_2
The myocardial cell apoptosis models of rats were established, that is, myocardial H9c2 cells was exposed to 100μmol/L H_2O_2 at 6 h. FK506 were administerted to the model group at low dose (0.15μmol/L) and high dose (0.60μmol/L) levels, and the apoptotic and necrotic rates were detected by FCM with AnnexinⅤ/PI double fluorescent staining. Compared with 100μmol/L H_2O_2-exposed group at 1 h, the H_2O_2-induced apoptotic rate was significantly decreased in FK506 treated group (P < 0.05). The inhibitor of CaN shows protective effect on myocardial H9c2 cell apoptosis induced by H_2O_2, with dose-undependant manner.
3. The protective effect on myocardial ischemia/reperfusion injury of inhibitor of CaN in rats
3.1 A rat heart model of ischemia/reperfusion injury established Weigh and anesthetized the rat , then fix it on the operation table and removed the fur from the neck and the left chest. The trachea was intubated and arterial blood pressure was continuously monitored via a saline-filled catheter inserted into the common carotid artery. The chest was opened and the pericardium was incised. The heart was gently exteriorized by applying pressure on the right side of the chest, and a ligature wa placed around the left anterior descending coronary (LAD) occlusion 30 min and reperfusion 120 min. Then a rat model of myocardial ischemia/reperfusion injury was been established. Wistar rats were randomly divided into four groups: I/R group, FK506-I/R group (FK506 was intravenouosly injected 15 min before ischemia), Sham group (a ligature was placed around LAD and no occluded), FK506-Sham group (FK506 was intravenously injected , a ligature was placed around LAD and no occluded).
3.2 Monitoring mean blood pressure, heart rate and electrocardiogram Mean blood pressure (MBP) was continuously monitored via an pressure transducer connected to a physiograph. Electrocardiogram and heart rate (HR) are measured by LeadⅡusing an electrocardiogram/rate coupler, both being analyzed by the BL-410 BioLab System. Four period of MBP and HR were selected (baseline, before occlusion, end-ischemia, end-reperfusion). Evaluation of arrhythmias were based on the description of the Lambeth Conventions. Total number of episodes for premature ventricular contraction (PVC), total duration for ventricular tachycardia (VT) and ventricular fibrillation (VF) were evaluated. The severity of arrythmias was quantified by a scoring system. During the ischemia period, MBP was a significant decrease in I/R group compared with in FK506-I/R group (P < 0.05). But during the reperfusion period, these two groups were no significant difference (P > 0.05). During the four period, the changes of HR were not obvious. Administration of FK506 before I/R significantly reduced the occurrence of PVC, VT, VF and duration of cardiac arrhythmia, and reduced the arrhythmia score (P > 0.05). The results suggest FK506 shows antiarrhythmic and cardioprotective effects in rat model of myocardial ischemia/reperfusion injury.
3.3 Area at risk myocardial infarct size determination
The area at risk (ischemic/reperfused region) and the infarct size were measured using Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining method. The images of heart slices were captured by a camera and area of infarcted myocardium was digitally measured using Image-Pro plus. Area-at-risk (AAR)/left-ventricular area (LV)×100%, infarct zone (IS)/LV×100%, IS/AAR×100% were calculated. Compared with I/R group, IS/AAR in FK506-I/R group was singnificant decrease (P < 0.05). The result indicated FK506 signifivantly reduced myocardial ischemia/reperfusion injury.
3.4 Assay of myocardial enzyme leakage
At the end of reperfusion, blood samples were collected to measure the myocardial enzyme leakage, including creatinine kinase (CK) and lactate dehydrogenase (LDH). CK and LDH kits were applied to examine their activities. It was showed the activities of CK and LDH were siginificant decrease in FK506-I/R group compared with I/R group (P < 0.05).
3.5 Lipid peroxidation of plasma examination
SOD kit was applied to examine activities of SOD in rats plasma. It was showed the activities of SOD were significant decrease in both FK506-I/R and I/R groups, compared with Sham group (P < 0.05). There were no significant changes from FK506-I/R to I/R group(P > 0.05). TBA colorimetric method was applied to examine MDA contents. It was showed the MDA contents were significant increase in both FK506-I/R and I/R groups, compared with Sham group (P < 0.05). There were no significant changes from FK506-I/R to I/R group(P > 0.05).
3.6 Changes of CaN enzyme activites
CaN kit was applied to examine activites of CaN in myocardium tissues. The activities of CaN were significant decrease in FK506-I/R group compared with I/R group(P < 0.05).
4. CaN induced myocardiocyte apoptosis caused by ischemia/reperfusion indury and related mechanism.
4.1 Changes of expression of Bcl-2, Bax, and Caspase– 3 Immunocytochemical method was used to detect expression of Bax, Bcl-2 and Caspase-3. It could be observed under optical microscope that nucleus of positive expressed cells was dyed dark blue and cytoplasm or cellular membrane was dyed brown. Expression of Bcl-2 significantly increased in FK506-I/R group, and expression of Bax significantly increased in I/R group compared with Sham group(P < 0.05). The value of Bcl-2/Bax were a significant difference between FK506-I/R and I/R group(P < 0.05). Expression of Caspase-3 was a significant increase in FK506-I/R and I/R group compared Sham group (P < 0.05). The result suggests FK506 could depress myocardiocyte apoptosis.
4.2 Changes of expression of CaN
Western blot was applied to detect CaN activity, and the characteristic 62 kDa fragment of CaN was observed in four groups. The expression of CaN enhanced and got to the highest in I/R group, the lowest in FK506-Sham group.
Generally, H_2O_2 could cause oxidative injury and DNA damage. It could also cause mitochondrial damage, then decrease mitochondrial mambrane potential. So H_2O_2 could induce the apoptosis on myocardial H9c2 cells. The inhibitor of CaN, FK506, could suppress H_2O_2-induced apoptosis on the H9c2 cells, and shows cardioprotective effect . FK506 could reduce the size of infarct zone on a rat model of myocardial ischemia/reperfusion injury, and increase the expression of Bcl-2 protein. So the inhibitor of CaN could suppress myocardiocyte apoptosis, the mechanism is related to CaN production and induced apoptosis by mitochondria signal transduction.
After an acute ischemic heart disease, early and successful myocardial reperfusion is an effictive strategy for obtaining thoroughly coronary blood flow, saving the dying myocardiocyte and reducing the size of a myocardial infarct. Because of the uncertainty relates to the ischemic period and degree, myocardial ischemia/reperfusion injury caused by the restoration of coroary blood flow after an ischemic episode. This form of myocardial injury can induce cardiomyocyte apoptosis and necrosis, increase infarct size, remodel cardiac ventricle, then the ultmate incidence is cardiac failure. To observe H_2O_2-induced myocardial H9c2 cell apoptosis and pretective effect of inhibitor of calcineurin (CaN), a cell apoptotic model from rat myocardiocytes cell line H9c2 induced by hydrogen dioxide (H_2O_2) and a rat model of ischemia/reperfusion are established. These provide theoretical basis for study on CaN induced myocardiocyte apoptosis caused by ischemia/reperfusion indury and related mechanism.
1.Toxicity of H_2O_2 on H9c2 cells
1.1 The survival rate of H9c2 cell detected by MTT MTT assay was performed to detect the toxicity after 1, 3, 6, 12 and 24 h exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L). It was showed the survival rate decreased with the increase of dosage and duration of exposure to H_2O_2. After 6 h exposure to 200μmol/L H_2O_2,half of the H9c2 cells died. The change of survival rate was over 60%, with 24 h after exposure 400μmol/L H_2O_2. There was significant difference in survival rate between H_2O_2 group and control group(NC) (P < 0.05). The results suggest that cardiomyocytes are sensitive to H_2O_2-induced dosage.
1.2 DNA damage of H9c2 cells
Single cell gel electrophoresis (SCGE) assay was used to examine DNA damage of H9c2 cells 6 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L). When exposed to 50, 100, 200 and 400μmol/L H_2O_2 for 6 h, there were significant difference from control group. The results suggest H_2O_2 could cause DNA damage of myocardiocytes in dose dependant way.
1.3 Apoptosis detected by AO/EB double fluorescent staining assay There were distinctive changes on cell apoptosis observed under fluorescence microscope 1, 3, 6 and 12 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L) by AO/EB double staining. The H9c2 cells occur obviously morphological changes in H_2O_2 -exposed groups, and the apoptotic rate was a significant increase compared with control group (P < 0.05), the highest group at 6 h after exposure to 100μmol/L H_2O_2. Whthin a prolong time exposure to it, the change of apoptotic rate is not obvious.
1.4 Apoptosis detected by FCM with AnnexinⅤ/PI double fluorescent staining Cell apoptosis was observed by FCM 1, 6 and 24 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L). The apoptotic rates were significantly increased in 100, 200 and 400μmol/L H_2O_2 at 6 and 24 h compared with control group(P < 0.05), the highest group at 24 h after exposure to 400μmol/L H_2O_2. The results suggest H_2O_2 could induce the H9c2 cell apoptosis in dose dependant and time dependant way.
1.5 Membrane potential detected by FCM with Rhodamine 123 fluorescent prode
Mitochondria membrane potential (Δψmt) was observed by FCM 1, 6 and 24 h after exposure to H_2O_2 (0, 50, 100, 200 and 400μmol/L).Δψmt showed the significant increase in H_2O_2 -exposed groups at 1 h compared with control group (P < 0.05). Whthin a prolong time exposure to it, the change ofΔψmt is observed. Compared with control group,Δψmt showed the significant increase in 50 and 100μmol/L H_2O_2 at 6 h, and the significant decrease in 200 and 400μmol/L H_2O_2 at 24h (P < 0.05). The results suggest H_2O_2 could damage mitochondria, decreaseΔψmt and induce the apoptosis in myocardial H9c2 cell.
2. Effect of inhibitor of calcineurin on myocardial H9c2 cell apoptosis induced by H_2O_2
The myocardial cell apoptosis models of rats were established, that is, myocardial H9c2 cells was exposed to 100μmol/L H_2O_2 at 6 h. FK506 were administerted to the model group at low dose (0.15μmol/L) and high dose (0.60μmol/L) levels, and the apoptotic and necrotic rates were detected by FCM with AnnexinⅤ/PI double fluorescent staining. Compared with 100μmol/L H_2O_2-exposed group at 1 h, the H_2O_2-induced apoptotic rate was significantly decreased in FK506 treated group (P < 0.05). The inhibitor of CaN shows protective effect on myocardial H9c2 cell apoptosis induced by H_2O_2, with dose-undependant manner.
3. The protective effect on myocardial ischemia/reperfusion injury of inhibitor of CaN in rats
3.1 A rat heart model of ischemia/reperfusion injury established Weigh and anesthetized the rat , then fix it on the operation table and removed the fur from the neck and the left chest. The trachea was intubated and arterial blood pressure was continuously monitored via a saline-filled catheter inserted into the common carotid artery. The chest was opened and the pericardium was incised. The heart was gently exteriorized by applying pressure on the right side of the chest, and a ligature wa placed around the left anterior descending coronary (LAD) occlusion 30 min and reperfusion 120 min. Then a rat model of myocardial ischemia/reperfusion injury was been established. Wistar rats were randomly divided into four groups: I/R group, FK506-I/R group (FK506 was intravenouosly injected 15 min before ischemia), Sham group (a ligature was placed around LAD and no occluded), FK506-Sham group (FK506 was intravenously injected , a ligature was placed around LAD and no occluded).
3.2 Monitoring mean blood pressure, heart rate and electrocardiogram Mean blood pressure (MBP) was continuously monitored via an pressure transducer connected to a physiograph. Electrocardiogram and heart rate (HR) are measured by LeadⅡusing an electrocardiogram/rate coupler, both being analyzed by the BL-410 BioLab System. Four period of MBP and HR were selected (baseline, before occlusion, end-ischemia, end-reperfusion). Evaluation of arrhythmias were based on the description of the Lambeth Conventions. Total number of episodes for premature ventricular contraction (PVC), total duration for ventricular tachycardia (VT) and ventricular fibrillation (VF) were evaluated. The severity of arrythmias was quantified by a scoring system. During the ischemia period, MBP was a significant decrease in I/R group compared with in FK506-I/R group (P < 0.05). But during the reperfusion period, these two groups were no significant difference (P > 0.05). During the four period, the changes of HR were not obvious. Administration of FK506 before I/R significantly reduced the occurrence of PVC, VT, VF and duration of cardiac arrhythmia, and reduced the arrhythmia score (P > 0.05). The results suggest FK506 shows antiarrhythmic and cardioprotective effects in rat model of myocardial ischemia/reperfusion injury.
3.3 Area at risk myocardial infarct size determination
The area at risk (ischemic/reperfused region) and the infarct size were measured using Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining method. The images of heart slices were captured by a camera and area of infarcted myocardium was digitally measured using Image-Pro plus. Area-at-risk (AAR)/left-ventricular area (LV)×100%, infarct zone (IS)/LV×100%, IS/AAR×100% were calculated. Compared with I/R group, IS/AAR in FK506-I/R group was singnificant decrease (P < 0.05). The result indicated FK506 signifivantly reduced myocardial ischemia/reperfusion injury.
3.4 Assay of myocardial enzyme leakage
At the end of reperfusion, blood samples were collected to measure the myocardial enzyme leakage, including creatinine kinase (CK) and lactate dehydrogenase (LDH). CK and LDH kits were applied to examine their activities. It was showed the activities of CK and LDH were siginificant decrease in FK506-I/R group compared with I/R group (P < 0.05).
3.5 Lipid peroxidation of plasma examination
SOD kit was applied to examine activities of SOD in rats plasma. It was showed the activities of SOD were significant decrease in both FK506-I/R and I/R groups, compared with Sham group (P < 0.05). There were no significant changes from FK506-I/R to I/R group(P > 0.05). TBA colorimetric method was applied to examine MDA contents. It was showed the MDA contents were significant increase in both FK506-I/R and I/R groups, compared with Sham group (P < 0.05). There were no significant changes from FK506-I/R to I/R group(P > 0.05).
3.6 Changes of CaN enzyme activites
CaN kit was applied to examine activites of CaN in myocardium tissues. The activities of CaN were significant decrease in FK506-I/R group compared with I/R group(P < 0.05).
4. CaN induced myocardiocyte apoptosis caused by ischemia/reperfusion indury and related mechanism.
4.1 Changes of expression of Bcl-2, Bax, and Caspase– 3 Immunocytochemical method was used to detect expression of Bax, Bcl-2 and Caspase-3. It could be observed under optical microscope that nucleus of positive expressed cells was dyed dark blue and cytoplasm or cellular membrane was dyed brown. Expression of Bcl-2 significantly increased in FK506-I/R group, and expression of Bax significantly increased in I/R group compared with Sham group(P < 0.05). The value of Bcl-2/Bax were a significant difference between FK506-I/R and I/R group(P < 0.05). Expression of Caspase-3 was a significant increase in FK506-I/R and I/R group compared Sham group (P < 0.05). The result suggests FK506 could depress myocardiocyte apoptosis.
4.2 Changes of expression of CaN
Western blot was applied to detect CaN activity, and the characteristic 62 kDa fragment of CaN was observed in four groups. The expression of CaN enhanced and got to the highest in I/R group, the lowest in FK506-Sham group.
Generally, H_2O_2 could cause oxidative injury and DNA damage. It could also cause mitochondrial damage, then decrease mitochondrial mambrane potential. So H_2O_2 could induce the apoptosis on myocardial H9c2 cells. The inhibitor of CaN, FK506, could suppress H_2O_2-induced apoptosis on the H9c2 cells, and shows cardioprotective effect . FK506 could reduce the size of infarct zone on a rat model of myocardial ischemia/reperfusion injury, and increase the expression of Bcl-2 protein. So the inhibitor of CaN could suppress myocardiocyte apoptosis, the mechanism is related to CaN production and induced apoptosis by mitochondria signal transduction.
引文
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