氧化低密度脂蛋白与胰岛素样生长因子-1促进血管平滑肌细胞生物学改变的信号转导机制及药物干预作用
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摘要
目的：探讨氧化低密度脂蛋白(oxLDL)，胰岛素样生长因子-1(IGF-1)促血管平滑肌细胞(VSMC)增殖及分泌功能改变的细胞内信号转导机制及三羟基三甲基戊二酰辅酶A抑制剂阿托伐他汀(atorvastatin)与免疫抑制剂雷帕霉素(Rapamycin)干预作用。
方法：兔血管平滑肌细胞分8组处理，即对照组、药物组(阿托伐他汀或雷帕霉素)、阿托伐他汀+羟甲戊酸组、低密度脂蛋白组(LDL)、丝裂因子组(oxLDL或IGF-1)、药物+因子组、P13K特异性抑制剂Wortmannin(WT)组及WT+丝裂因子组。以细胞计数、噻唑蓝比色法测定细胞增殖能力，酶联免疫法检测培养上清液中细胞因子TNFa、IL-6、IL-8水平，Western免疫印记定量蛋白激酶B、蛋白磷酸酶PTEN表达水平，免疫沉淀、特异底物组蛋白H2BY~(32)P掺入量测定PKB活性，特异底物dic16PIP3脱磷酸绿色试剂法反应PTEN活性。
结果：oxLDL(50μg／ml)、IGF-1(100ng／ml)分别可使细胞计数及MTT比色OD值增加1.78，3.2及2.8、3.8倍，而LDL(50μg／ml)无明显作用。WT本身可使上述细胞增殖指标分别降至对照组的69％、61.25％、71.4％、68.7％，并使oxLDL、IGF-1的促增殖作用降至对照组水平。各浓度oxLDL、IGF-1及盯对PKB及PTEN蛋白表达水平均无明显影响。oxLDL可浓度(5～50μg／ml)、时间(3分钟至24小时)依赖地增加PKB活性，时间曲线呈双峰、于10分钟达高峰，为对照组的15.37倍，其后逐渐降低，至8小时再度升至10.1倍、24小时时较8小时活性为低，但仍达对照组的6.92倍(均p＜0.01)，同等浓度的LDL未见PKB活性改变。IGF-1对PKB活性影响的浓度效应出现于1ng／ml时，100ng／ml作用10分钟活性达对照组的57.25倍，其后进行性降低，24小时仍保持在5.47倍(均p＜0.001)。WT对PKB活性的影响也呈时间依赖性，预孵育20分钟后降至76％，至24小时达38％，并可使上述oxLDL及IGF-1增加的PKB活性降至正常水平或更低。PTEN磷酸酶活性测定表明，oxLDL及IGF-1对其活性的抑制分别在20～50μg／ml及10～100ng／ml范围内呈浓度依赖性。时间曲线表现为10分钟作用最强，并可持续达24小时(均p＜0.01)。oxLDL及IGF-1对TNFQ、IL-6、IL-8分泌水平的增加
军医进修学院博士学位论文 第5页共81页
于刺激后1小时即增至1．2～1．4倍（分别P＞0．05，P＜0．of，P＜0．01），8小时达
6．4～8．5倍，24小时仍高达1．26～5．05倍（均P＜0．01）。阿托伐他汀及雷帕霉素
干预实验表明，两者均可显著抑制细胞增殖活性，并完全逆转。XLDL及IGF－l的促
增殖作用。阿托伐他汀及雷帕霉素在浓度分别为0．05～luM及10～100nM范围内使
PKB活性，细胞因子分泌等呈浓度依赖性降低，至最大浓度时其PKB活性降低均
＞70％（均 P＜0．of）。胆固醇前体羟甲戊酸与阿托伐他汀共同孵育细胞可阻止后者
的上述抑制VSMC增殖及细胞因子分泌作用。
结论 PI3K／PKB信号通路是兔 VSMC增殖及分泌细胞因子 TNFQ、IL－6和
几－8的重耍信号转导系统，。XLDL及IGF－卫可能通过对生长信号PI3K／PKB的活化
及负性调节蛋白PTEN磷酸酶的抑制发挥促进VSMC增殖及分泌的功能。他汀类药物
阿托伐他汀及大环内酯类免疫抑制剂雷帕霉素可能通过抑制PI3K／PKB信号通路对
VSMC生物学功能发挥较全面调控效用。此项研究不仅为研制 PI3K／PTEN／PKB调节
药物用于以细胞过度增生为主要病理改变的疾病治疗展示了可能途径，更为该两种
药物在冠心病一、二级预防或冠脉介入治疗后再狭窄防治中取得的理想疗效提供了
理论支持。对动脉粥样硬化与再狭窄机制，以及他汀类药物和雷帕霉素等分子药理
学的全面、系统研究，必将对该类疾病的防治决策产生深刻影响。
Objective: To investigate the cellular signal transudation pathway of vascular smooth muscle cell (VSMC) proliferation and cytokins secretion stimulated by oxidized low density lipoprotein(oxLDL) and insulin-like growth factor-1(IGF-1) and the intervention effect of HMG-coA reductase inhibitor, atovastatin and immune supppressor .rapamycin.
Methods: Rabbit aortic VSMC was cultured in 8 groups:control; native low density lipoprotein (LDL); mitogensCoxLDL or IGF-1); drugs(atorvastatin or rapamycin); PI3K(phosphatidylinositol 3-kinase) specific inhibitor , wortmannin(WT); drugs plus mitogens; WT plus mitogens; atorvastatin plus mevalonate(MVA). Cell proliferating ability was determined by measuring cell number and mitochondrial dehydrogenase (MD)activity(MTT assay).The level of tumor necrosis factore alpha(TNF a ), interleukin-6(IL-6) and interleukin~8(IL-8) were evaluated using ELISA method. Western blotting was used to detect the protein expression of protein kinase B(PKB) and lipid phosphatase PTEN . Immunoprecipitations and radioactivity of y 32P incorporated into its specific substrate histon HzB was utilized to determine the PKB activation. Phosphate concentration released from PTEN-specific substrat diC16PIP3 was assessed using green reagent method.
Results: oxLDL(50 u g/ml)and IGF-1(lOOng/ml) increased cell number and MD activity to 1. 78~3. 8 fold, but the same concentration of LDL has no such mitogenic effect. WT itself decreased the above parameters to
69%, 61.25%, 71.4% and 68.7% of control group (p<0.001) and completely reversed the proliferation-promoting effect of both oxLDL and IGF-1. oxLDL elevated PKB activity in a concentration-(5~50 P g/ml) and time-(3min. ~ 24h)dependent manner. 5 P g/ml of oxLDL caused a 1.95-fold increase in PKB activity,whereas the maximum dose of oxLDL(50 n g/ml) induced a 15.37-fold increase within 10 minutes. The time course was characterized by two peaks, the first appeared within 10 minutes, the second at 8 hours with a 10.1-fold increase and still as high as 6.92-fold in 24 hours. The concentration effect of IGF-1 on PKB activity emerged at 1.0 ng/ml and reached to the maximum of 57.25-fold at 100 ng/ml in 10 minutes, followed by continual decrease to 5.47-fold in 24 hours (p<0.001). The effect of WT on PKB activity was also time dependent, reaching to 76% after 20 minutes preincubation and keeping decreasing to 38% in 24 hours. Phosphatase activity detection show that the dephosphate action of PTEN was inhibited by oxLDL(20~50 u g/ml) and IGF-1(10 ~ lOOng/ml) in a concentration dependent manner, and this inhibiting effect was at its maximum within 10 minutes, lasting at least for 24 hours(p<0. 001). WT abolished the mitogenic effects of oxLDL and IGF~1 on PKB activity. Cytokins evaluation demenstrated that the promoting effect of oxLDL and IGF-1 on the secretion of TNF a ,IL-6 and IL-8 was rapid,causing a 1. 2~1.4-fold increase within Ih , reached to peak of 6. 4~ 8. 5-fold and sustained as high as 1.26~5.05-fold in 24 hours. WT decreased these cytokin's level to that of control group and abolish the above secretion promoting effects of the two mitogens. Drug intervention experiment show that both atorvastatin and rapamycin can markedly inhibit VSMC proliferation and completely abolish the mitogenic effect of oxLDL and IGF-1. In a concentration range of 0. 05~luM and 10~ lOOng/ml separetly, atorvastatin and rapamycin can decrease the PKB activity in a concentration dependent manner, with a more than 70% decrease at the highest concentration. Coincubation with cholesterol precurssor MVA completely reversed all the above effects of atorvastatin. Conclusions: PI3K/PTEN/PKB signal transduction system is one of the crucial signal pathway involved in rabbit VSMC proliferation and
secretion of TNF a , IL~6 and IL-8 stimulated with or without oxLDL and IGF-l.oxLDL and IGF-1 can also inhibit the phosphatase activity of PTEN which dephosphate PIPS and thus regulate the PKB activity adversely. Both atorvastatin and rapamycin can inhibit cell proliferation, cytok
方法：兔血管平滑肌细胞分8组处理，即对照组、药物组(阿托伐他汀或雷帕霉素)、阿托伐他汀+羟甲戊酸组、低密度脂蛋白组(LDL)、丝裂因子组(oxLDL或IGF-1)、药物+因子组、P13K特异性抑制剂Wortmannin(WT)组及WT+丝裂因子组。以细胞计数、噻唑蓝比色法测定细胞增殖能力，酶联免疫法检测培养上清液中细胞因子TNFa、IL-6、IL-8水平，Western免疫印记定量蛋白激酶B、蛋白磷酸酶PTEN表达水平，免疫沉淀、特异底物组蛋白H2BY~(32)P掺入量测定PKB活性，特异底物dic16PIP3脱磷酸绿色试剂法反应PTEN活性。
结果：oxLDL(50μg／ml)、IGF-1(100ng／ml)分别可使细胞计数及MTT比色OD值增加1.78，3.2及2.8、3.8倍，而LDL(50μg／ml)无明显作用。WT本身可使上述细胞增殖指标分别降至对照组的69％、61.25％、71.4％、68.7％，并使oxLDL、IGF-1的促增殖作用降至对照组水平。各浓度oxLDL、IGF-1及盯对PKB及PTEN蛋白表达水平均无明显影响。oxLDL可浓度(5～50μg／ml)、时间(3分钟至24小时)依赖地增加PKB活性，时间曲线呈双峰、于10分钟达高峰，为对照组的15.37倍，其后逐渐降低，至8小时再度升至10.1倍、24小时时较8小时活性为低，但仍达对照组的6.92倍(均p＜0.01)，同等浓度的LDL未见PKB活性改变。IGF-1对PKB活性影响的浓度效应出现于1ng／ml时，100ng／ml作用10分钟活性达对照组的57.25倍，其后进行性降低，24小时仍保持在5.47倍(均p＜0.001)。WT对PKB活性的影响也呈时间依赖性，预孵育20分钟后降至76％，至24小时达38％，并可使上述oxLDL及IGF-1增加的PKB活性降至正常水平或更低。PTEN磷酸酶活性测定表明，oxLDL及IGF-1对其活性的抑制分别在20～50μg／ml及10～100ng／ml范围内呈浓度依赖性。时间曲线表现为10分钟作用最强，并可持续达24小时(均p＜0.01)。oxLDL及IGF-1对TNFQ、IL-6、IL-8分泌水平的增加
军医进修学院博士学位论文 第5页共81页
于刺激后1小时即增至1．2～1．4倍（分别P＞0．05，P＜0．of，P＜0．01），8小时达
6．4～8．5倍，24小时仍高达1．26～5．05倍（均P＜0．01）。阿托伐他汀及雷帕霉素
干预实验表明，两者均可显著抑制细胞增殖活性，并完全逆转。XLDL及IGF－l的促
增殖作用。阿托伐他汀及雷帕霉素在浓度分别为0．05～luM及10～100nM范围内使
PKB活性，细胞因子分泌等呈浓度依赖性降低，至最大浓度时其PKB活性降低均
＞70％（均 P＜0．of）。胆固醇前体羟甲戊酸与阿托伐他汀共同孵育细胞可阻止后者
的上述抑制VSMC增殖及细胞因子分泌作用。
结论 PI3K／PKB信号通路是兔 VSMC增殖及分泌细胞因子 TNFQ、IL－6和
几－8的重耍信号转导系统，。XLDL及IGF－卫可能通过对生长信号PI3K／PKB的活化
及负性调节蛋白PTEN磷酸酶的抑制发挥促进VSMC增殖及分泌的功能。他汀类药物
阿托伐他汀及大环内酯类免疫抑制剂雷帕霉素可能通过抑制PI3K／PKB信号通路对
VSMC生物学功能发挥较全面调控效用。此项研究不仅为研制 PI3K／PTEN／PKB调节
药物用于以细胞过度增生为主要病理改变的疾病治疗展示了可能途径，更为该两种
药物在冠心病一、二级预防或冠脉介入治疗后再狭窄防治中取得的理想疗效提供了
理论支持。对动脉粥样硬化与再狭窄机制，以及他汀类药物和雷帕霉素等分子药理
学的全面、系统研究，必将对该类疾病的防治决策产生深刻影响。
Objective: To investigate the cellular signal transudation pathway of vascular smooth muscle cell (VSMC) proliferation and cytokins secretion stimulated by oxidized low density lipoprotein(oxLDL) and insulin-like growth factor-1(IGF-1) and the intervention effect of HMG-coA reductase inhibitor, atovastatin and immune supppressor .rapamycin.
Methods: Rabbit aortic VSMC was cultured in 8 groups:control; native low density lipoprotein (LDL); mitogensCoxLDL or IGF-1); drugs(atorvastatin or rapamycin); PI3K(phosphatidylinositol 3-kinase) specific inhibitor , wortmannin(WT); drugs plus mitogens; WT plus mitogens; atorvastatin plus mevalonate(MVA). Cell proliferating ability was determined by measuring cell number and mitochondrial dehydrogenase (MD)activity(MTT assay).The level of tumor necrosis factore alpha(TNF a ), interleukin-6(IL-6) and interleukin~8(IL-8) were evaluated using ELISA method. Western blotting was used to detect the protein expression of protein kinase B(PKB) and lipid phosphatase PTEN . Immunoprecipitations and radioactivity of y 32P incorporated into its specific substrate histon HzB was utilized to determine the PKB activation. Phosphate concentration released from PTEN-specific substrat diC16PIP3 was assessed using green reagent method.
Results: oxLDL(50 u g/ml)and IGF-1(lOOng/ml) increased cell number and MD activity to 1. 78~3. 8 fold, but the same concentration of LDL has no such mitogenic effect. WT itself decreased the above parameters to
69%, 61.25%, 71.4% and 68.7% of control group (p<0.001) and completely reversed the proliferation-promoting effect of both oxLDL and IGF-1. oxLDL elevated PKB activity in a concentration-(5~50 P g/ml) and time-(3min. ~ 24h)dependent manner. 5 P g/ml of oxLDL caused a 1.95-fold increase in PKB activity,whereas the maximum dose of oxLDL(50 n g/ml) induced a 15.37-fold increase within 10 minutes. The time course was characterized by two peaks, the first appeared within 10 minutes, the second at 8 hours with a 10.1-fold increase and still as high as 6.92-fold in 24 hours. The concentration effect of IGF-1 on PKB activity emerged at 1.0 ng/ml and reached to the maximum of 57.25-fold at 100 ng/ml in 10 minutes, followed by continual decrease to 5.47-fold in 24 hours (p<0.001). The effect of WT on PKB activity was also time dependent, reaching to 76% after 20 minutes preincubation and keeping decreasing to 38% in 24 hours. Phosphatase activity detection show that the dephosphate action of PTEN was inhibited by oxLDL(20~50 u g/ml) and IGF-1(10 ~ lOOng/ml) in a concentration dependent manner, and this inhibiting effect was at its maximum within 10 minutes, lasting at least for 24 hours(p<0. 001). WT abolished the mitogenic effects of oxLDL and IGF~1 on PKB activity. Cytokins evaluation demenstrated that the promoting effect of oxLDL and IGF-1 on the secretion of TNF a ,IL-6 and IL-8 was rapid,causing a 1. 2~1.4-fold increase within Ih , reached to peak of 6. 4~ 8. 5-fold and sustained as high as 1.26~5.05-fold in 24 hours. WT decreased these cytokin's level to that of control group and abolish the above secretion promoting effects of the two mitogens. Drug intervention experiment show that both atorvastatin and rapamycin can markedly inhibit VSMC proliferation and completely abolish the mitogenic effect of oxLDL and IGF-1. In a concentration range of 0. 05~luM and 10~ lOOng/ml separetly, atorvastatin and rapamycin can decrease the PKB activity in a concentration dependent manner, with a more than 70% decrease at the highest concentration. Coincubation with cholesterol precurssor MVA completely reversed all the above effects of atorvastatin. Conclusions: PI3K/PTEN/PKB signal transduction system is one of the crucial signal pathway involved in rabbit VSMC proliferation and
secretion of TNF a , IL~6 and IL-8 stimulated with or without oxLDL and IGF-l.oxLDL and IGF-1 can also inhibit the phosphatase activity of PTEN which dephosphate PIPS and thus regulate the PKB activity adversely. Both atorvastatin and rapamycin can inhibit cell proliferation, cytok
引文
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