胰岛素介导SHR VSMC增殖的基因外修饰机制研究
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摘要
一、研究背景
大量研究证实高血压合并糖尿病及高胰岛素血症的病人,发生心脑血管并发症的风险大大高于单纯高血压病人,动物实验与基础研究证实:1、胰岛素可诱发实验动物动脉硬化的发生;2、在超生理浓度下,胰岛素刺激血管平滑肌细胞的增生和迁移;3、长期给与外源胰岛素导致脂异常与动脉壁增厚;4、胰岛素输注加速了输注动脉的粥样硬化。提示胰岛素抵抗及其代偿性的高胰岛素血症是冠心病的重要危险因素,在冠心病和血管增生性疾病的预防和治疗过程中也说明高胰岛素血症在血管增生性病变中发生重要作用。积极改善胰岛素抵抗和高胰岛素血症,对以上的疾病将起到积极的防治作用。
二、研究目的
明确结构基因外修饰对血管平滑肌细胞增殖及表型转换的影响,找出胰岛素介导血管平滑肌细胞异常增殖时基因外改变(结构基因外修饰)调控细胞增殖的变化规律及结构基因外修饰和细胞增殖相关基因表达差异之间的内在联系及作用机制,揭示血管平滑肌细胞增殖的机制,为血管增生性疾病的防治寻求新的理论和实验依据。
三、研究内容
1.胰岛素促SHR VSMCs增殖的MAPK机制。
2.丁酸钠阻断HDAC后组蛋白超乙酰化对SHR VSMCs增殖的影响。
3.胰岛素对组蛋白乙酰化的影响,PD98059阻断MAPK通路后组蛋白乙酰化的改变。
4.胰岛素对HDAC1的作用及PD98059阻断MAPK后对这种作用的影响。
5.丁酸钠导致的组蛋白超乙酰化对MAPK通路的影响。
6.胰岛素对增殖相关因子PDGF基因转录及蛋白表达的影响及PD98059和丁酸钠对胰岛素的这种作用的影响。
7.胰岛素对VSMCs表型相关蛋白质α-SM actin、OPN表达的影响及PD98059和丁酸钠对其的作用。
8.胰岛素、PD98059、丁酸钠对PDGF和α-SM actin DNA启动子甲基化的影响。
四、研究方法
1.原代培养SHR VSMCs。
2. H3-TdR掺入、MTT法、细胞计数法、流式细胞仪检测VSMCs的增殖情况。
3.建立胰岛素促VSMCs增殖的浓度曲线。
4.以胰岛素及PD98059干预VSMC后观察VSMCs增殖的情况,免疫印迹和RT-PCR观察MAPK蛋白质表达及mRNA表达的变化。
5.丁酸钠干预VSMCs后对胰岛素促VSMC增殖作用的影响。
6.免疫印迹检测胰岛素、PD98059、丁酸钠对VSMCs HDAC1及组蛋白乙酰化的影响。
7.免疫印迹检测胰岛素、PD98059、丁酸钠对MAPK表达的影响,RT-PCR检测其对MAPK基因转录的作用。
8.免疫印迹检测胰岛素、PD98059、丁酸钠对PDGF和α-SM actin表达的影响,RT-PCR检测其对PDGF和α-SM actin基因转录的作用。
9.特异性甲基化DNA PCR检测胰岛素、PD98059、丁酸钠对PDGF和α-SM actin DNA启动子甲基化的影响。
五、研究结果
1.胰岛素能够明显促进MAPK的表达及SHR VSMCs增殖,且这种作用能被PD98059阻断。
2.丁酸钠能抑制胰岛素促进SHR VSMCs增殖的作用。
3.胰岛素促进HDAC1的表达,丁酸钠明显抑制HDAC1的表达,PD98059对HDAC1的表达无明显影响。
4.免疫印迹显示胰岛素促进组蛋白H3乙酰化,而PD98059抑制胰岛素的这种作用。
5.胰岛素上调PDGF的表达,同时下调α-SM actin的表达。该作用可被PD98059和丁酸钠阻断。
6.胰岛素促进MAPK、PDGF基因的转录,同时抑制α-SM actin基因的转录,该作用可被PD98059和丁酸钠阻断。
7. PDGF DNA启动子在SHR VSMCs中生理情况下处于非甲基化状态,胰岛素、PD98059对其非甲基化状态没有影响,但丁酸钠可以使PDGF DNA启动子发生甲基化。
8.α-SM actin DNA启动子在SHR VSMCs中生理情况下处于非甲基化状态,胰岛素、PD98059、丁酸钠对其非甲基化状态均没有产生影响。
六、结论
1.胰岛素介导SHR VSMCs增殖经由MAPK信号传导途径。
2.组蛋白乙酰化的改变参与了胰岛素介导SHR VSMCs增殖的过程,且这种过程通过MAPK信号传导途径。
3.胰岛素介导SHR VSMCs增殖没有α-SM actin及PDGF DNA启动子甲基化状态的改变参与,但丁酸钠抑制SHR VSMCs增殖可能涉及PDGF DNA启动子的甲基化改变。
1. Background
Previous studies show that the risk of cardiovascular complications in hypertensive patients with diabetes and hyperinsulinemia is much high. Animal experiments and basic researches have documented that 1) atherosclerosis could be induced by insulin in laboratory animals; 2) the proliferation and migration of vascular smooth muscle cells (VSMC) are increased by insulin at super-physiological concentrations; 3) long-term application of insulin leads to abnormal lipid metabolism and thickening of artery vessel wall; 4) infusion of insulin accelerates the progress of atherosclerosis in the infused artery. All the above-mentioned studies indicate that insulin resistance and compensatory hyperinsulinemia are the major risk factors for coronary heart disease. Moreover, prevention and treatment of coronary heart disease and vascular proliferative disease also show the importance of hyperinsulinemia in the process of vascular proliferative lesions. Improvement of the insulin sensitivity would be benefit to protect from coronary artery disease and other vascular diseases.
2. Objectives
This study is to identify the effects of epigenetic modification on proliferation and phenotype conversion of vascular smooth muscle cells, to investigate the role of cell proliferation mediated by insulin-induced epigenetic modification, the internal relations and the mechanisms of different expressions between epigenetic modification and cell proliferation related genes, and to reveal the mechanisms of proliferation of vascular smooth muscle cells, to explore new theoretical and experimental basis for prevention and control of vascular proliferative diseases.
3. Study contents
1) The role of MAPK in the proliferation of VSMCs induced by insulin.
2) Effect of histone super-acetylation on proliferation of VSMCs after blockade of HDAC with sodium butyrate.
3) Effect of insulin on histone acetylation and investigation of histone acetylation after blockade of MAPK with PD98059.
4) Effect of insulin on HDAC1 with or without blockade of MAPK with PD98059.
5) Effect of histone super-acetylation-induced by sodium butyrate on MAPK pathway.
6) Effect of insulin on genetic transcription and protein expression of proliferation related gene PDGF before and after treatment of PD98059 and sodium butyrate.
7) Effect of insulin on expressions ofα-SM actin and OPN before and after treatment of PD98059 and sodium butyrate.
8) Effect of insulin, PD98059 and sodium butyrate on promoter methylation of PDGF andα-SM actin DNA.
4. Methods and materials
1) Primary culture of VSMCs from SHRs.
2) Proliferation of VSMCs determined by H3-TdR, MTT, cytometry and flow cytometry.
3) Establishment of concentration curve of insulin-mediated proliferation of VSMCs.
4) To observe the effects of insulin and PD98059 on VSMCs proliferation and MAPK expression determined by immunoblotting and RT-PCR.
5) Effect of sodium butyrate on proliferation of VSMCs induced by insulin.
6) Effect of insulin, PD98059 and sodium butyrate on HDAC1 and histone acetylization of VSMCs determined by immunoblotting.
7) Effect of insulin, PD98059 and sodium butyrate on MAPK protein and mRNA expressions determined by immunoblotting and RT-PCR.
8) Effect of insulin, PD98059 and sodium butyrate on PDGF andα-SM actin protein and mRNA expressions determined by immunoblotting and RT-PCR.
9) Effect of insulin, PD98059 and sodium butyrate on promoter methylation of PDGF andα-SM actin DNA determined by specific DNA methylation PCR.
5. Results
1) Insulin increased MAPK expression and proliferation of VSMCs, which was blocked by PD98059.
2) Sodium butyrate inhibited the insulin-mediated proliferation of VSMCs.
3) Insulin increased, while sodium butyrate decreased HDAC1 expression, PD98059 had no effect on HDAC1 expression.
4) Insulin increased, while PD98059 decreased the acetylation of histone H3 determined by immunoblotting.
5) Insulin up-regulated the expression of PDGF, down-regulatedα-SM actin expression, which was blocked by PD98059 and sodium butyrate.
6) Insulin increased the genetic transcription of MAPK and PDGF, decreased the gene transcription ofα-SM actin, which was blocked by PD98059 and sodium butyrate.
7) PDGF DNA promoter was non-methylation in physical condition in VSMCs from SHRs; sodium butyrate, instead of PD98059 and insulin, increased methylation of PDGF DNA.
8)α-SM actin DNA promoter was non-methylation status in physical condition in VSMCs from SHRs; sodium butyrate, PD98059 and insulin had no effect on this non-methoylation status.
6. Conclusions
1) The MAPK pathway is involved in the insulin-mediated proliferation of VSMCs from SHRs
2) Histone acetylation is engaged into the insulin-mediated proliferation of VSMCs from SHRs, MAPK pathway is involved into this action.
3) Proliferation of VSMCs from SHRs induced by insulin is not related toα-SM actin and PDGF DNA promoter methylation but effect of sodium butyrate on proliferation of VSMCs from SHRs might be related to PDGF DNA promoter methylation.
大量研究证实高血压合并糖尿病及高胰岛素血症的病人,发生心脑血管并发症的风险大大高于单纯高血压病人,动物实验与基础研究证实:1、胰岛素可诱发实验动物动脉硬化的发生;2、在超生理浓度下,胰岛素刺激血管平滑肌细胞的增生和迁移;3、长期给与外源胰岛素导致脂异常与动脉壁增厚;4、胰岛素输注加速了输注动脉的粥样硬化。提示胰岛素抵抗及其代偿性的高胰岛素血症是冠心病的重要危险因素,在冠心病和血管增生性疾病的预防和治疗过程中也说明高胰岛素血症在血管增生性病变中发生重要作用。积极改善胰岛素抵抗和高胰岛素血症,对以上的疾病将起到积极的防治作用。
二、研究目的
明确结构基因外修饰对血管平滑肌细胞增殖及表型转换的影响,找出胰岛素介导血管平滑肌细胞异常增殖时基因外改变(结构基因外修饰)调控细胞增殖的变化规律及结构基因外修饰和细胞增殖相关基因表达差异之间的内在联系及作用机制,揭示血管平滑肌细胞增殖的机制,为血管增生性疾病的防治寻求新的理论和实验依据。
三、研究内容
1.胰岛素促SHR VSMCs增殖的MAPK机制。
2.丁酸钠阻断HDAC后组蛋白超乙酰化对SHR VSMCs增殖的影响。
3.胰岛素对组蛋白乙酰化的影响,PD98059阻断MAPK通路后组蛋白乙酰化的改变。
4.胰岛素对HDAC1的作用及PD98059阻断MAPK后对这种作用的影响。
5.丁酸钠导致的组蛋白超乙酰化对MAPK通路的影响。
6.胰岛素对增殖相关因子PDGF基因转录及蛋白表达的影响及PD98059和丁酸钠对胰岛素的这种作用的影响。
7.胰岛素对VSMCs表型相关蛋白质α-SM actin、OPN表达的影响及PD98059和丁酸钠对其的作用。
8.胰岛素、PD98059、丁酸钠对PDGF和α-SM actin DNA启动子甲基化的影响。
四、研究方法
1.原代培养SHR VSMCs。
2. H3-TdR掺入、MTT法、细胞计数法、流式细胞仪检测VSMCs的增殖情况。
3.建立胰岛素促VSMCs增殖的浓度曲线。
4.以胰岛素及PD98059干预VSMC后观察VSMCs增殖的情况,免疫印迹和RT-PCR观察MAPK蛋白质表达及mRNA表达的变化。
5.丁酸钠干预VSMCs后对胰岛素促VSMC增殖作用的影响。
6.免疫印迹检测胰岛素、PD98059、丁酸钠对VSMCs HDAC1及组蛋白乙酰化的影响。
7.免疫印迹检测胰岛素、PD98059、丁酸钠对MAPK表达的影响,RT-PCR检测其对MAPK基因转录的作用。
8.免疫印迹检测胰岛素、PD98059、丁酸钠对PDGF和α-SM actin表达的影响,RT-PCR检测其对PDGF和α-SM actin基因转录的作用。
9.特异性甲基化DNA PCR检测胰岛素、PD98059、丁酸钠对PDGF和α-SM actin DNA启动子甲基化的影响。
五、研究结果
1.胰岛素能够明显促进MAPK的表达及SHR VSMCs增殖,且这种作用能被PD98059阻断。
2.丁酸钠能抑制胰岛素促进SHR VSMCs增殖的作用。
3.胰岛素促进HDAC1的表达,丁酸钠明显抑制HDAC1的表达,PD98059对HDAC1的表达无明显影响。
4.免疫印迹显示胰岛素促进组蛋白H3乙酰化,而PD98059抑制胰岛素的这种作用。
5.胰岛素上调PDGF的表达,同时下调α-SM actin的表达。该作用可被PD98059和丁酸钠阻断。
6.胰岛素促进MAPK、PDGF基因的转录,同时抑制α-SM actin基因的转录,该作用可被PD98059和丁酸钠阻断。
7. PDGF DNA启动子在SHR VSMCs中生理情况下处于非甲基化状态,胰岛素、PD98059对其非甲基化状态没有影响,但丁酸钠可以使PDGF DNA启动子发生甲基化。
8.α-SM actin DNA启动子在SHR VSMCs中生理情况下处于非甲基化状态,胰岛素、PD98059、丁酸钠对其非甲基化状态均没有产生影响。
六、结论
1.胰岛素介导SHR VSMCs增殖经由MAPK信号传导途径。
2.组蛋白乙酰化的改变参与了胰岛素介导SHR VSMCs增殖的过程,且这种过程通过MAPK信号传导途径。
3.胰岛素介导SHR VSMCs增殖没有α-SM actin及PDGF DNA启动子甲基化状态的改变参与,但丁酸钠抑制SHR VSMCs增殖可能涉及PDGF DNA启动子的甲基化改变。
1. Background
Previous studies show that the risk of cardiovascular complications in hypertensive patients with diabetes and hyperinsulinemia is much high. Animal experiments and basic researches have documented that 1) atherosclerosis could be induced by insulin in laboratory animals; 2) the proliferation and migration of vascular smooth muscle cells (VSMC) are increased by insulin at super-physiological concentrations; 3) long-term application of insulin leads to abnormal lipid metabolism and thickening of artery vessel wall; 4) infusion of insulin accelerates the progress of atherosclerosis in the infused artery. All the above-mentioned studies indicate that insulin resistance and compensatory hyperinsulinemia are the major risk factors for coronary heart disease. Moreover, prevention and treatment of coronary heart disease and vascular proliferative disease also show the importance of hyperinsulinemia in the process of vascular proliferative lesions. Improvement of the insulin sensitivity would be benefit to protect from coronary artery disease and other vascular diseases.
2. Objectives
This study is to identify the effects of epigenetic modification on proliferation and phenotype conversion of vascular smooth muscle cells, to investigate the role of cell proliferation mediated by insulin-induced epigenetic modification, the internal relations and the mechanisms of different expressions between epigenetic modification and cell proliferation related genes, and to reveal the mechanisms of proliferation of vascular smooth muscle cells, to explore new theoretical and experimental basis for prevention and control of vascular proliferative diseases.
3. Study contents
1) The role of MAPK in the proliferation of VSMCs induced by insulin.
2) Effect of histone super-acetylation on proliferation of VSMCs after blockade of HDAC with sodium butyrate.
3) Effect of insulin on histone acetylation and investigation of histone acetylation after blockade of MAPK with PD98059.
4) Effect of insulin on HDAC1 with or without blockade of MAPK with PD98059.
5) Effect of histone super-acetylation-induced by sodium butyrate on MAPK pathway.
6) Effect of insulin on genetic transcription and protein expression of proliferation related gene PDGF before and after treatment of PD98059 and sodium butyrate.
7) Effect of insulin on expressions ofα-SM actin and OPN before and after treatment of PD98059 and sodium butyrate.
8) Effect of insulin, PD98059 and sodium butyrate on promoter methylation of PDGF andα-SM actin DNA.
4. Methods and materials
1) Primary culture of VSMCs from SHRs.
2) Proliferation of VSMCs determined by H3-TdR, MTT, cytometry and flow cytometry.
3) Establishment of concentration curve of insulin-mediated proliferation of VSMCs.
4) To observe the effects of insulin and PD98059 on VSMCs proliferation and MAPK expression determined by immunoblotting and RT-PCR.
5) Effect of sodium butyrate on proliferation of VSMCs induced by insulin.
6) Effect of insulin, PD98059 and sodium butyrate on HDAC1 and histone acetylization of VSMCs determined by immunoblotting.
7) Effect of insulin, PD98059 and sodium butyrate on MAPK protein and mRNA expressions determined by immunoblotting and RT-PCR.
8) Effect of insulin, PD98059 and sodium butyrate on PDGF andα-SM actin protein and mRNA expressions determined by immunoblotting and RT-PCR.
9) Effect of insulin, PD98059 and sodium butyrate on promoter methylation of PDGF andα-SM actin DNA determined by specific DNA methylation PCR.
5. Results
1) Insulin increased MAPK expression and proliferation of VSMCs, which was blocked by PD98059.
2) Sodium butyrate inhibited the insulin-mediated proliferation of VSMCs.
3) Insulin increased, while sodium butyrate decreased HDAC1 expression, PD98059 had no effect on HDAC1 expression.
4) Insulin increased, while PD98059 decreased the acetylation of histone H3 determined by immunoblotting.
5) Insulin up-regulated the expression of PDGF, down-regulatedα-SM actin expression, which was blocked by PD98059 and sodium butyrate.
6) Insulin increased the genetic transcription of MAPK and PDGF, decreased the gene transcription ofα-SM actin, which was blocked by PD98059 and sodium butyrate.
7) PDGF DNA promoter was non-methylation in physical condition in VSMCs from SHRs; sodium butyrate, instead of PD98059 and insulin, increased methylation of PDGF DNA.
8)α-SM actin DNA promoter was non-methylation status in physical condition in VSMCs from SHRs; sodium butyrate, PD98059 and insulin had no effect on this non-methoylation status.
6. Conclusions
1) The MAPK pathway is involved in the insulin-mediated proliferation of VSMCs from SHRs
2) Histone acetylation is engaged into the insulin-mediated proliferation of VSMCs from SHRs, MAPK pathway is involved into this action.
3) Proliferation of VSMCs from SHRs induced by insulin is not related toα-SM actin and PDGF DNA promoter methylation but effect of sodium butyrate on proliferation of VSMCs from SHRs might be related to PDGF DNA promoter methylation.
引文
我国人群高血压(Essential Hypertension, EH)的患病率呈持续增长趋势,2002年卫生部组织的全国居民27万人营养和健康状况调查资料显示,随着我国居民膳食结构的改变,人群中慢性非传染性疾病患病率迅速上升,我国18岁以上居民EH患病率达18.8%,估计全国患病人数1.6亿多。与1991年相比,患病率上升了31%[1、2]。我国目前每15秒就有一人死于心脑血管病,心脑血管病的总发病率和死亡率已接近发达国家。2004年卫生部统计资料表明心脑血管病死亡率占死亡构成的44.4%,居死亡原因首位,EH为死亡的第一位危险因素。EH和相关疾病造成的经济负担巨大,2003年统计显示我国EH直接医疗费为300亿元,EH和相关疾病造成的直接和间接的耗费每年估计为3000亿元[1、2]。冠心病合并糖尿病患者中伴高血压、脑卒中、高脂血症家族史较非糖尿病冠心病患者现况调查发现空腹胰岛素水平最高组的既往心梗发生率和冠脉造影证实的冠脉明显狭窄均显著高于空腹胰岛素水平最低组[3]。大量研究证实高血压合并糖尿病及高胰岛素血症的病人,发生心脑血管并发症的风险大大高于单纯高血压病人,动物实验与基础研究证实:1、胰岛素可诱发实验动物动脉硬化的发生;2、在超生理浓度下,胰岛素刺激血管平滑肌细胞的增殖和迁移;3、长期给予外源胰岛素导致脂异常与动脉壁增厚;4、胰岛素输注加速了输注动脉的粥样硬化。提示胰岛素抵抗及其代偿性的高胰岛素血症是冠心病的重要危险因素,在冠心病和血管增生性疾病的预防和治疗过程中也说明高胰岛素血症在血管增生性病变中发生重要作用。积极改善胰岛素抵抗和高胰岛素血症,对以上的疾病产生将起到积极的防治作用。
在以往对胰岛素引起血管平滑肌细胞(VSMC)异常增殖的研究中发现,自发性高血压大鼠(SHR)血管平滑肌细胞内胰岛素介导的PKC亚型(ɑ、β、δ)可从胞浆转位到膜上,并使丝裂原活化蛋白激酶(MAPK)的活性增加,即激活PKC-MAPK细胞信号传导途径,使细胞内原癌基因c-fos表达增加,进一步用基因芯片和二维蛋白电泳技术发现VSMC经胰岛素刺激后的增殖不仅是单一原癌基因c-fos表达增高,而是多种与VSMC增殖及相关基因表达差异有关。实验证实胰岛素-MAPK介导VSMC异常增殖及表型转换
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在以往对胰岛素引起血管平滑肌细胞(VSMC)异常增殖的研究中发现,自发性高血压大鼠(SHR)血管平滑肌细胞内胰岛素介导的PKC亚型(ɑ、β、δ)可从胞浆转位到膜上,并使丝裂原活化蛋白激酶(MAPK)的活性增加,即激活PKC-MAPK细胞信号传导途径,使细胞内原癌基因c-fos表达增加,进一步用基因芯片和二维蛋白电泳技术发现VSMC经胰岛素刺激后的增殖不仅是单一原癌基因c-fos表达增高,而是多种与VSMC增殖及相关基因表达差异有关。实验证实胰岛素-MAPK介导VSMC异常增殖及表型转换
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