SIRT1通过调节氧化应激参与老年COPD大鼠心脏损伤的机制研究
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摘要
目的：以老年COPD大鼠为模型观察COPD诱导心脏损伤的改变,研究SIRT1调控COPD诱导心脏氧化应激损伤的机制,探讨SIRT1激动剂白藜芦醇在老年COPD:大鼠心脏氧化应激损伤中的保护作用。
方法：动物实验1.3月龄及22月龄雄性SD大鼠,分为青年对照组(12只)、青年COPD组(12只)、老年对照组(12只)、老年COPD(11只)、老年COPD+白藜芦醇(Rrsveratrol, Res)组(12只)。两年龄组中的COPD组及COPD+Res组大鼠于实验第1、25天气管内注入脂多糖(Lipopolysaccharide, LPS) 200μg/200μl,第2-24天、26-56天被动吸烟。老年COPD+Res组大鼠提前2天给与白藜芦醇25/mg/d灌药至实验结束。共8周。2.测量各组大鼠体重、左心室重量、心脏超声；漂浮导管测量右心室压(Right Ventricular Pressure, RVP)、肺动脉压(Pulmonary Arterial Pressure, PAP)及左心室舒张末压(Left Ventricular End Diastolic Pressure, LVEDP); HE染色观察心脏病理、Masson染色明确心肌间质胶原纤维增生情况,透射电镜检测心肌超微结构改变；试剂盒检测各组大鼠心肌丙二醛(malondialdehyde, MDA)、超氧化物歧化酶(superoxide dismutase, SOD)水平；免疫组化检测心肌8-羟基脱氧鸟苷(8-hydroxy-2'-deoxyguanine,8-OHdG)的表达；末端脱氧核酸转移酶介导的d-UDP缺口末端标记(Terminal deoxynucleotidyl transferase-mediated d-UDP nickendlabelling, TUNEL)法检测心肌细胞凋亡情况。Taqman探针荧光定量PCR检测各组大鼠心肌SIRT1的mRNA表达,Weston Blot检测大鼠心肌SIRT1和p-FOXO3a的蛋白表达。细胞实验1.H9C2细胞分为对照组(C组)、溶剂对照组(DMSO组)、香烟提取液(Cigarette Smoke Extract, CSE)刺激组(CSE组)、CSE+Res组、Res组。CSE干预组给予CSE25μg/ml干预3-72小时,Res用药组提前30分钟给予Res 20μmol/L, DMSO组给予与Res等量的DMSO。2.噻唑蓝(MTT)法检测细胞增殖情况；特异性荧光探针CM-H2DCFDA和荧光微量平板法检测ROS的表达；荧光分光光度计检测细胞线粒体膜电位,试剂盒检测各组细胞半胱氨酸蛋白酶-3(caspase-3)活性;Taqman探针荧光定量PCR检测各组细胞SIRT1的mRNA表达,Weston Blot检测各组细胞SIRT1和p-FOXO3a的表达。
结果：第一部分1.青年、老年COPD模型的肺部病理改变符合COPD的特点。2.与老年对照组相比,老年COPD组心肌间质胶原纤维含量升高(P<0.01)。左室舒张末径(Left Ventricular End-Diastolic Dimension, LVEDD)、LVEDP显著升高(P<0.05),8-OHdG表达显著升高(P<0.01),MDA增加(P<0.01),SOD活性下降(P<0.01)。
第二部分体内实验1.与老年对照组大鼠相比,老年COPD组大鼠SIRT1 mRNA、蛋白表达均降低(P<0.05),p-FOXO3a蛋白表达降低(P<0.05)；心肌细胞凋亡数量增加(P<0.05)；2.与与老年COPD组大鼠相比,老年COPD+Res组大鼠SIRT1 mRNA.蛋白表达均升高(P<0.05),p-FOXO3a蛋白表达升高(P<0.05)。心肌间质胶原纤维含量下降(P<0.01),LVEDD下降(P<0.05)。8-OHdG的表达显著降低(P<0.05),MDA水平降低(P<0.05),SOD活性升高(P<0.05)；心肌细胞凋亡数量显著减少(P<0.05)。体外实验1.与C组相比,CSE刺激组SIRT1mRNA及蛋白相对表达量、p-FOXO3a蛋白相对表达量均显著降低(P<0.01)；与CSE组相比,CSE+Res组SIRT1mRNA、蛋白相对表达量及p-FOXO3a蛋白相对表达量升高(P＜0.05)。2.随CSE刺激浓度增加,H9C2产生ROS增加；提前给予Res后ROS产生减少(P＜0.05)。3.与C组相比,CSE组ROS表达显著增强(P<0.01),caspase-3活性显著增加(P<0.01)；CSE+Res组与CSE组相比,ROS表达减弱(P<0.01)；caspase-3活性显著降低(P<0.01)。
第三部分体内实验老年COPD组线粒体结构严重破坏,嵴消失。老年COPD+Res组线粒体结构损伤减轻。体外实验随CSE刺激浓度增加,H9C2细胞的线粒体膜电位降低,提前给予Res可以使线粒体膜电位升高(P<0.01)。
结论：1.老年COPD大鼠发生心室重塑加重、心功能受损,与氧化应激损伤有关;2.SIRT1通过影响心肌线粒体膜电位调节线粒体ROS的产生,可能是SIRT1参与COPD大鼠心脏氧化应激损伤的调控机制之一;3. SIRT1参与COPD大鼠心脏氧化应激损伤的调控机制可能还与p-FOXO3a表达改变有关,有待于进一步研究；4.白藜芦醇通过刺激SIRT1的表达减轻心脏氧化应激和凋亡,可在COPD大鼠心脏损伤中发挥保护作用。
Objective. To study the injuries of heart induced by Chronic Obstructive Pulmonary Disease (COPD) in old rats; 2. To Observe the oxidative stress modulation mechanisms of SIRT1 during this process; 3. To explore how resveratrol and SIRT1 exert antioxidant, antiapoptotic effects, which protect the heart against the adverse effects of COPD induced by cigarette smoking exposure and LPS.
Methods. In vivo experiments, SD rats at 3-month-old and 22-month-old were divided into five groups:the young control group (12), the young COPD group (12), the old control group (12), the old COPD group (11), the old COPD group treated with resveratrol (COPD+Res) group (12). ALL of the COPD groups (n= 35) were exposed to the smoke of 8 commercial cigarettes (11 mg tar and 0.8 mg nicotine/cigarette) each day for 8 weeks and instillation given of LPS 200μg/200μl twice, whereas the control group was not exposed to cigarette smoking. To assess the heart protective effects of resveratrol, the COPD+Res group of rats was pretreated with resveratrol 25 mg-kg-1·day-1for 8 weeks and then exposed to the above-described cigarette smoking protocol. The changes of weight, heart weight, LVEF,LVEDD, RVP, PAP, LVEDP, SOD, MDA,8-OHdG, collagen, cadiocyte apoptosis were detected. The expression of SIRT1 were evalulated by Taqman real-time RT-PCR and Western Blot. The expression of p-FOXO3a were evalulated by Western blot. In vitro Experiments 1. H9C2 cells were divided into control group (C group), solvent control group (DMSO group), cigarette smoking extraction stimulus group (CSE group), CSE group with Res treatment group (CSE+Res group) and Res group.25μg/ml CSE intervened to CSE group from 3-72h and Res group was pre treated with 20μmol/L Res 30min before. Res group was treated with the equal amount of Res.2. Cell proliferation was investigated by MTT method and the CSE concentration was determined. Specific fluorescent probe CM-H2DCFDA and fluorescent micro-plate method was employed for the determination of ROS expression. Mitochondrial membrane potential was measured by fluorescence spectrophotometer and the level of apoptosis was measured by activity of caspase 3. RT-PCR was employed for the determination of the expression of SIRT1 mRNA.The protein of SIRT1 and p-FOXO3a expressions were observed by Weston Blot.
Results Part 1 1.The changes in histopathology of lung in rats of the two COPD groups were similary to those in COPD pantients.2.Compared with old rats in control group, the obvious increase were found in HW/BW, thickness of left ventricle, diameter of cadiocyte, collagen, LVEDD, PAP, LVEDP,8-OHdG and MDA in rats of old COPD group (P<0.01), and significantly decrease were found in SOD (P<0.01). It was found more hypertrophy changes in the HE-stained myocardial cells of old COPD group than that of old control group, while we also found the myocardial fibrosis significantly increased by masson staining. Part 2 In vivo experiments 1. Compared with rats in old control group, the expression of SIRT1mRNA and protein decreased in rats of old COPD group (P<0.05), the expression of SIRT1 staining by immunofluorescence decreased, and the expression of p-FOXO3a protein decreased (P<0.05).2. Compared with rats in old COPD group, the expression of SIRT1mRNA and protein increased in old COPD+Res group (P<0.05), the expression of SIRT1 staining by immunefluorescence increased, and the expression of p-FOXO3a protein increased (P<0.05).3.Compared with rats in old COPD group, the obvious decrease were found in thickness of left ventricle, diameter of cadiocyte, collagen, LVEDD, PAP, LVEDP, 8-OHdG and MDA of old COPD+Res group (P<0.05),and significantly increase were found in SOD (P<0.01).4.Compared with old control group, the apoptosis index of cardiac muscle increased in old COPD group (P<0.05).The apoptosis index decreased in old COPD+Res group as opposed to old COPD group (P<0.05). In vitro experiments 1. The expression of ROS increased in H9C2 cells of CSE group against the cells of C group (P<0.05), whereas and the expression of SIRT1 and p-FOXO3a decreased (P<0.05), the activity of caspase-3 increased(P<0.05)in CSE group; 2.The expression of ROS decreased in CSE+Res group as compared with the H9C2 cells of CSE group (P<0.05), the activity of caspase-3 also was found decreased (P< 0.05), and the expression of SIRT1 and p-FOXO3a increased (P<0.05). Part 3 In vivo experiments 1.The more severe damage of chondriosome was found in old COPD group than that of old control group, while the damage of chondriosome significantly lessen in Res treated group. In vitro experiments 1.The mitochondria membrane potential drop (P<0.05) in CSE group, whereas can be increased by Res (P<0.05)
Conclusion 1. The left ventricular remodeling and heart dysfunction can be induced by oxidative stress in old COPD rat.2. SIRT1 may be regulate the oxidative stress in old COPD rat by the effect on ROS production of mitochondria in the cardiac.3. p-FOXO3a may also involved in the oxidative stress regulation in the heart injury induced by COPD with SIRT1.4. The myocardial protection of resveratrol against COPD related stress may be by inducing expression of SIRT1. Rresveratrol may be considered as anti-oxidative stress therapy for the heart injury in old COPD rat.
方法：动物实验1.3月龄及22月龄雄性SD大鼠,分为青年对照组(12只)、青年COPD组(12只)、老年对照组(12只)、老年COPD(11只)、老年COPD+白藜芦醇(Rrsveratrol, Res)组(12只)。两年龄组中的COPD组及COPD+Res组大鼠于实验第1、25天气管内注入脂多糖(Lipopolysaccharide, LPS) 200μg/200μl,第2-24天、26-56天被动吸烟。老年COPD+Res组大鼠提前2天给与白藜芦醇25/mg/d灌药至实验结束。共8周。2.测量各组大鼠体重、左心室重量、心脏超声；漂浮导管测量右心室压(Right Ventricular Pressure, RVP)、肺动脉压(Pulmonary Arterial Pressure, PAP)及左心室舒张末压(Left Ventricular End Diastolic Pressure, LVEDP); HE染色观察心脏病理、Masson染色明确心肌间质胶原纤维增生情况,透射电镜检测心肌超微结构改变；试剂盒检测各组大鼠心肌丙二醛(malondialdehyde, MDA)、超氧化物歧化酶(superoxide dismutase, SOD)水平；免疫组化检测心肌8-羟基脱氧鸟苷(8-hydroxy-2'-deoxyguanine,8-OHdG)的表达；末端脱氧核酸转移酶介导的d-UDP缺口末端标记(Terminal deoxynucleotidyl transferase-mediated d-UDP nickendlabelling, TUNEL)法检测心肌细胞凋亡情况。Taqman探针荧光定量PCR检测各组大鼠心肌SIRT1的mRNA表达,Weston Blot检测大鼠心肌SIRT1和p-FOXO3a的蛋白表达。细胞实验1.H9C2细胞分为对照组(C组)、溶剂对照组(DMSO组)、香烟提取液(Cigarette Smoke Extract, CSE)刺激组(CSE组)、CSE+Res组、Res组。CSE干预组给予CSE25μg/ml干预3-72小时,Res用药组提前30分钟给予Res 20μmol/L, DMSO组给予与Res等量的DMSO。2.噻唑蓝(MTT)法检测细胞增殖情况；特异性荧光探针CM-H2DCFDA和荧光微量平板法检测ROS的表达；荧光分光光度计检测细胞线粒体膜电位,试剂盒检测各组细胞半胱氨酸蛋白酶-3(caspase-3)活性;Taqman探针荧光定量PCR检测各组细胞SIRT1的mRNA表达,Weston Blot检测各组细胞SIRT1和p-FOXO3a的表达。
结果：第一部分1.青年、老年COPD模型的肺部病理改变符合COPD的特点。2.与老年对照组相比,老年COPD组心肌间质胶原纤维含量升高(P<0.01)。左室舒张末径(Left Ventricular End-Diastolic Dimension, LVEDD)、LVEDP显著升高(P<0.05),8-OHdG表达显著升高(P<0.01),MDA增加(P<0.01),SOD活性下降(P<0.01)。
第二部分体内实验1.与老年对照组大鼠相比,老年COPD组大鼠SIRT1 mRNA、蛋白表达均降低(P<0.05),p-FOXO3a蛋白表达降低(P<0.05)；心肌细胞凋亡数量增加(P<0.05)；2.与与老年COPD组大鼠相比,老年COPD+Res组大鼠SIRT1 mRNA.蛋白表达均升高(P<0.05),p-FOXO3a蛋白表达升高(P<0.05)。心肌间质胶原纤维含量下降(P<0.01),LVEDD下降(P<0.05)。8-OHdG的表达显著降低(P<0.05),MDA水平降低(P<0.05),SOD活性升高(P<0.05)；心肌细胞凋亡数量显著减少(P<0.05)。体外实验1.与C组相比,CSE刺激组SIRT1mRNA及蛋白相对表达量、p-FOXO3a蛋白相对表达量均显著降低(P<0.01)；与CSE组相比,CSE+Res组SIRT1mRNA、蛋白相对表达量及p-FOXO3a蛋白相对表达量升高(P＜0.05)。2.随CSE刺激浓度增加,H9C2产生ROS增加；提前给予Res后ROS产生减少(P＜0.05)。3.与C组相比,CSE组ROS表达显著增强(P<0.01),caspase-3活性显著增加(P<0.01)；CSE+Res组与CSE组相比,ROS表达减弱(P<0.01)；caspase-3活性显著降低(P<0.01)。
第三部分体内实验老年COPD组线粒体结构严重破坏,嵴消失。老年COPD+Res组线粒体结构损伤减轻。体外实验随CSE刺激浓度增加,H9C2细胞的线粒体膜电位降低,提前给予Res可以使线粒体膜电位升高(P<0.01)。
结论：1.老年COPD大鼠发生心室重塑加重、心功能受损,与氧化应激损伤有关;2.SIRT1通过影响心肌线粒体膜电位调节线粒体ROS的产生,可能是SIRT1参与COPD大鼠心脏氧化应激损伤的调控机制之一;3. SIRT1参与COPD大鼠心脏氧化应激损伤的调控机制可能还与p-FOXO3a表达改变有关,有待于进一步研究；4.白藜芦醇通过刺激SIRT1的表达减轻心脏氧化应激和凋亡,可在COPD大鼠心脏损伤中发挥保护作用。
Objective. To study the injuries of heart induced by Chronic Obstructive Pulmonary Disease (COPD) in old rats; 2. To Observe the oxidative stress modulation mechanisms of SIRT1 during this process; 3. To explore how resveratrol and SIRT1 exert antioxidant, antiapoptotic effects, which protect the heart against the adverse effects of COPD induced by cigarette smoking exposure and LPS.
Methods. In vivo experiments, SD rats at 3-month-old and 22-month-old were divided into five groups:the young control group (12), the young COPD group (12), the old control group (12), the old COPD group (11), the old COPD group treated with resveratrol (COPD+Res) group (12). ALL of the COPD groups (n= 35) were exposed to the smoke of 8 commercial cigarettes (11 mg tar and 0.8 mg nicotine/cigarette) each day for 8 weeks and instillation given of LPS 200μg/200μl twice, whereas the control group was not exposed to cigarette smoking. To assess the heart protective effects of resveratrol, the COPD+Res group of rats was pretreated with resveratrol 25 mg-kg-1·day-1for 8 weeks and then exposed to the above-described cigarette smoking protocol. The changes of weight, heart weight, LVEF,LVEDD, RVP, PAP, LVEDP, SOD, MDA,8-OHdG, collagen, cadiocyte apoptosis were detected. The expression of SIRT1 were evalulated by Taqman real-time RT-PCR and Western Blot. The expression of p-FOXO3a were evalulated by Western blot. In vitro Experiments 1. H9C2 cells were divided into control group (C group), solvent control group (DMSO group), cigarette smoking extraction stimulus group (CSE group), CSE group with Res treatment group (CSE+Res group) and Res group.25μg/ml CSE intervened to CSE group from 3-72h and Res group was pre treated with 20μmol/L Res 30min before. Res group was treated with the equal amount of Res.2. Cell proliferation was investigated by MTT method and the CSE concentration was determined. Specific fluorescent probe CM-H2DCFDA and fluorescent micro-plate method was employed for the determination of ROS expression. Mitochondrial membrane potential was measured by fluorescence spectrophotometer and the level of apoptosis was measured by activity of caspase 3. RT-PCR was employed for the determination of the expression of SIRT1 mRNA.The protein of SIRT1 and p-FOXO3a expressions were observed by Weston Blot.
Results Part 1 1.The changes in histopathology of lung in rats of the two COPD groups were similary to those in COPD pantients.2.Compared with old rats in control group, the obvious increase were found in HW/BW, thickness of left ventricle, diameter of cadiocyte, collagen, LVEDD, PAP, LVEDP,8-OHdG and MDA in rats of old COPD group (P<0.01), and significantly decrease were found in SOD (P<0.01). It was found more hypertrophy changes in the HE-stained myocardial cells of old COPD group than that of old control group, while we also found the myocardial fibrosis significantly increased by masson staining. Part 2 In vivo experiments 1. Compared with rats in old control group, the expression of SIRT1mRNA and protein decreased in rats of old COPD group (P<0.05), the expression of SIRT1 staining by immunofluorescence decreased, and the expression of p-FOXO3a protein decreased (P<0.05).2. Compared with rats in old COPD group, the expression of SIRT1mRNA and protein increased in old COPD+Res group (P<0.05), the expression of SIRT1 staining by immunefluorescence increased, and the expression of p-FOXO3a protein increased (P<0.05).3.Compared with rats in old COPD group, the obvious decrease were found in thickness of left ventricle, diameter of cadiocyte, collagen, LVEDD, PAP, LVEDP, 8-OHdG and MDA of old COPD+Res group (P<0.05),and significantly increase were found in SOD (P<0.01).4.Compared with old control group, the apoptosis index of cardiac muscle increased in old COPD group (P<0.05).The apoptosis index decreased in old COPD+Res group as opposed to old COPD group (P<0.05). In vitro experiments 1. The expression of ROS increased in H9C2 cells of CSE group against the cells of C group (P<0.05), whereas and the expression of SIRT1 and p-FOXO3a decreased (P<0.05), the activity of caspase-3 increased(P<0.05)in CSE group; 2.The expression of ROS decreased in CSE+Res group as compared with the H9C2 cells of CSE group (P<0.05), the activity of caspase-3 also was found decreased (P< 0.05), and the expression of SIRT1 and p-FOXO3a increased (P<0.05). Part 3 In vivo experiments 1.The more severe damage of chondriosome was found in old COPD group than that of old control group, while the damage of chondriosome significantly lessen in Res treated group. In vitro experiments 1.The mitochondria membrane potential drop (P<0.05) in CSE group, whereas can be increased by Res (P<0.05)
Conclusion 1. The left ventricular remodeling and heart dysfunction can be induced by oxidative stress in old COPD rat.2. SIRT1 may be regulate the oxidative stress in old COPD rat by the effect on ROS production of mitochondria in the cardiac.3. p-FOXO3a may also involved in the oxidative stress regulation in the heart injury induced by COPD with SIRT1.4. The myocardial protection of resveratrol against COPD related stress may be by inducing expression of SIRT1. Rresveratrol may be considered as anti-oxidative stress therapy for the heart injury in old COPD rat.
引文
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