重组Psilencer1.0-U6-siRNA-STAT3对动脉化静脉壁内膜异常增生抑制作用的实验研究
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摘要
临床上,冠状动脉旁路移植手术(CABG)是挽救冠状动脉粥样硬化性心脏病病人的重要措施。和自体的乳内动脉(IMA)相比,自体静脉中的大隐静脉(SV)是目前冠状动脉搭桥手术中的第二选择,但其缺点是远期阻塞率较高,术后阻塞发生率逐年增加,至术后10年全部阻塞率为35-40%。研究者发现其根本原因是由于血管重塑的结果以及新生内膜的形成,血管重塑包括细胞增殖,细胞凋亡,细胞迁移和降解以及细胞外基质的产生。
转录信号传导子及激活子通路(STATs)代表一条从膜到核的信号传导系统, STAT作用于细胞周期蛋白D1(CyclinD1)、B淋巴细胞瘤(Bcl-xL)等下游靶基因,调节细胞增殖、分化及凋亡。蛋白酪氨酸激酶(JAK)/STAT是一类具有复合效应和功能的信号通路,与其他细胞内信号通路有着复杂的交互关系,研究其与血管平滑肌细胞(VSMCs)病理生理功能之间的关系,可能为揭示以VSMCs增殖、迁移为发病核心环节的血管新生内膜形成、血管重塑等血管增殖性疾病的病理机制提供重要的实验基础和理论依据并指导临床治疗。
本研究利用经RNA干扰技术构建的针对STAT3通路的特异性质粒-Psilencer1.0-U6- siRNA-STAT3,来验证STAT3通路在VSMCs增殖中的作用;一、体外将该质粒通过脂质体Lipofectamine2000转染培养的大鼠主动脉平滑肌细胞(RSMCs),分为三组;对照组、空质粒组和实验组。共培养72小时可见,对照组和空质粒组的RSMC细胞数量明显高于实验组,细胞贴壁生长,状况良好,增殖旺盛,细胞间相互融合,呈“铺路石”样;细胞形态呈现梭形;而实验组RSMCs 48小时后则出现生长缓慢,细胞皱缩;部分细胞失去原有形态,细胞数目明显减少,折光性差。MTT检测显示实验组抑制率明显高于对照组和空质粒组。实验组的STAT3及其下游靶基因CyclnD1和Bcl-2的mRNA及蛋白的表达明显低于对照组。二、建立大鼠颈静脉移植模型,将其分为2组,对照组和实验组;并应用生物蛋白胶将质粒-脂质体混合物均匀的涂布于移植血管外膜。对照组血管内膜在术后明显增生,而实验组则增生不明显。同时实验组内膜增生的阳性细胞比例明显少于对照组。实验组移植血管STAT3及其下游靶基因CyclnD1和Bcl-2的mRNA及蛋白的表达明显低于对照组。该质粒确实通过对STAT3基因片段的转录翻译过程的抑制作用,阻断了其对下游靶基因CyclinD1和Bcl-2的作用,抑制了VSMCs的增殖,减轻了动脉化静脉壁血管的内膜增生。
Cardiovascular diseases due to atherosclerosis are the main reasons for deaths in the western world. For many patients with severe coronary disease,bypass-surgery is required. Veins are frequently used and have far better results compared with synthetic conduits. But Veins are not ideal bypass conduits which are reflected by the incidence of vein graft failure. Recent studies demonstrated that the primary patency of vein grafts was not better than 60-80 % within the first year after surgery treatment,and by the time when in the tenth year,the failure rate is 50%. A large amount of clinical and experimental studies have demonstrated that intimal thickening may lead to the restenosis of the vein graft. Proliferation and migration of vescular smooth muscle cells(VSMCs) may be a key contributor to neointimal formation. It was demonstrated in a canine vein graft model that the SMCs were transformed from contrictile to a secretory phenotype in response to vessel wall injury. By the switch of phenotypes the SMCs enter a state enabling proliferation,migration,and gain synthetic capacity,which is a pre-requisite for neointimal formation. It has been a well- supported opinion,that the source for the intimal cell population is SMCs from the media. Accumulating evidence sμggests that neointima formation is mediated by a complex interaction of a variety of growth regulatory molecules, such as growth factors,vasoactive peptides,inflammatory cytokines and chemokines.
However,it remains largely unknown which signaling pathways are responsible for neointima formation. STAT3,as one of the candidate signaling pathways,plays an important role in the SMCs proliferation and migration. STAT3 contains a conserved amino-terminal,aDNA-binding domain that binds specific interferon-activated DNA sequences,a SH-2 domain for receptor recruitment and STAT dimerization,and a transactivation domain. STAT3 protein is activated by a variety of stimuli. It is also involved in contradictory responses such as proliferation and apoptosis. Following activation,STAT3 protein changes conformation,forms homo- or hetero-dimers,and translocated from the cytoplasm to the nucleus. In the nucleus,STAT3 binds cis elements,which induce growth responsive and inflammatory genes; including junB,IRF-1,CyclinD1 and anti-apoptotic factors Bcl-xL and Bcl-2. In cultured rat SMCs , the STAT3 activation is substantially involved in the angiotensin II(AII)-or platelet-derived growth factor (PDGF)–induced proliferation.
To prevent restenosis of vein graft,extensive research has been conducted including standard technique of vein harvest and drug therapy et al,but these methods were not an ideal therapy. Two decades ago,gene therapy emerged since the first description of the site-directed transfer of exogenous genetic material into the vascular system .In initial experiments,vascular gene transfer were used to evaluate hypothesis by targeted overex- pression of selected proteins in the vasculature.Therefore,gene therapy as a potential strategy for the treatment of restenosis after angioplasty and vascular bypass graft has been extensively studied. Although effective delivery tools are remain to be solved,these reports sparked the anticipation that such approaches would be used for the therapeutic modulation of vascular responses,including stenosis after injury and restenosis.
In this study,the potential anti-proliferation effects of the recombinant plasmid- Psilencer1.0-U6-siRNA-STAT-3 on VSMCs in vitro and in vivo were investigated to find potential novel strategies for the treatment of restenosis after vein grafting. This plasmid is constructed by RNAi technique to aim at inhibiting mRNA expression and phosphorylation of STAT3. Following this process,Psilencer1.0-U6-siRNA-STAT-3 block the tranicription and translation of the downstream target genes-CyclnD1 and Bcl-2. By this mechanism,proliferation of VSMCs and the neointima formation are inhibited,and restenosis of transpl- anted vein graft is lessen or even blocked. Our study afford a theory base for anti-restenosis after coronary artery bypass graft on clinic.
Psilencer1.0-U6-siRNA-STAT-3 inhibited the proliferation of rat vascular smooth muscle cells in vitro
Methods:RSMCs (2×105 cells per well) seeded in 6-well culture plates were divided into 3 groups: the control group that no transfection were done; the scramble plasmid group in which the scramble plasmid transfected RSMCs and recombinant plasmid group in which RSMCs were transfected with Psilencer1.0-U6-siRNA-STAT-3. The lipofectamine 2000,as the vector,was mixed with plasmid (recombinant plasmid group or scramble)or itself at a proportionality of 0.5μl:0.2μg and added to the RSMCs .After coincubation for 72h,we use contrast phase microscope to observe the shape change of RSMCs; we added MTT solution (5 mg/mL in phosphate-buffered saline (PBS) to observe the proliferation capability of RSMCs; RT-PCR were examined to observe the mRNA expression of STAT3 and its downstream target gene CyclnD1 and Bcl-2; Western-blot were performed to observe expression of their fuctional products-protein.
Results:Observed with contrast phase microscope,Most RSMCs of the control group and scramble plasmid group are clostridial、anomalous triangle or fan shape with clear and intermediate nucleis and proliferate vigorous;however,RSMCs of Psilencer1.0-U6-siRNA- STAT3 group lost their intrinsical form and proliferated slowly with a pycnosis nucleis and some of them even floated in the culture bottle. By MTT assays,the proliferation of RSMCs in Psilencer1.0-U6-siRNA-STAT-3 group was significantly inhibited compared with the control group. RT-PCR detection show significantly decreased mRNA expression of STAT3、CyclnD1 and Bcl-2 in the Psilencer1.0-U6-siRNA-STAT-3 group,whereas the mRNA exepression of them were indistinguishable between the control and scramble plasmid group. Western-blot detection show that STAT3、Bcl-2 and CyclinD1 phosphorylation in the Psilencer1.0-U6-siRNA-STAT-3 group significantly declined compared with those of the control group.
Psilencer1.0-U6-siRNA-STAT-3 inhibited the proliferation of vascular smooth muscle cells in vivo
Methods:we constructed vein graft model and the Psilencer1.0-U6- siRNA- STAT-3/ lipofectamine2000 mixture were mixed with bioprotain gel (volume 80 ul) and sprayed to adventitia of vein graft. 168 free male wistar rats (250-350g) were divided into two groups: the control group (n=84) and recombinant plasmid(experiment)group (n = 84). On day 3、7、14 and 28 after operative procedure,the rats were killed. 5 of these interposed vein graft containing an adjacent section of the left carotid artery were harvested for morphological examination(HE) and immuno- histochemistry(PCNA); 8 of these interposed vein graft were harvested for RT-PCR detection and 8 for Western-blot assay.
Results:The intimal thickening on 3d post operative procedure had not much difference in the two groups,and it peaked on day 7 in the scramble plasmid group,while that in the recombinant plasmid group on day 7 had only scabrosity,on day 14 and 28,it had even no thickening in the experiment group. The thickness of intima had significant difference on day 7(12.3±0.21 and 6.7±0.25 respectively) and 14(7.2±0.31 and 4.6±0.14 respectively); PCNA index in the control group on day 7 and 14 were 31.3±4.7 and 27.2±5.7 respectively and that of experiment group were 23.3±2.8 and 15.6±0.4 respectively; there are significant deviation between the control and experiment group on day 7 and 14 of PCNA positive cells. RT-PCR detection shows that from day 3 after operative procedure,mRNA exepression of STAT3 and its downstream target gene CyclnD1 and Bcl-2 were showed in both the control and exeperiment group,and all peaked at 14d and declined to insignificant level at 28d. Compared with those of the control group,the mRNA expression of the experiment group on 7d decreased significantly. Immunoblotting studies showed that a transient STAT3 induction was accompanied with constitutive expression in the control group,The constitutive STAT3 phosphorylation was detected in the arterialized vein graft after day 3,peaked at day 7,and declined to insignificant levels at day 14. while in the experiment group,although STAT3 phosphorylation detected on day 3 was nearly the same as that in the control group,it was far lower than that of the control group on the 7d; and also that on day 7,CyclnD1 and Bcl-2 proteins level in the experiment group declined significantly compared with that of the control group.
转录信号传导子及激活子通路(STATs)代表一条从膜到核的信号传导系统, STAT作用于细胞周期蛋白D1(CyclinD1)、B淋巴细胞瘤(Bcl-xL)等下游靶基因,调节细胞增殖、分化及凋亡。蛋白酪氨酸激酶(JAK)/STAT是一类具有复合效应和功能的信号通路,与其他细胞内信号通路有着复杂的交互关系,研究其与血管平滑肌细胞(VSMCs)病理生理功能之间的关系,可能为揭示以VSMCs增殖、迁移为发病核心环节的血管新生内膜形成、血管重塑等血管增殖性疾病的病理机制提供重要的实验基础和理论依据并指导临床治疗。
本研究利用经RNA干扰技术构建的针对STAT3通路的特异性质粒-Psilencer1.0-U6- siRNA-STAT3,来验证STAT3通路在VSMCs增殖中的作用;一、体外将该质粒通过脂质体Lipofectamine2000转染培养的大鼠主动脉平滑肌细胞(RSMCs),分为三组;对照组、空质粒组和实验组。共培养72小时可见,对照组和空质粒组的RSMC细胞数量明显高于实验组,细胞贴壁生长,状况良好,增殖旺盛,细胞间相互融合,呈“铺路石”样;细胞形态呈现梭形;而实验组RSMCs 48小时后则出现生长缓慢,细胞皱缩;部分细胞失去原有形态,细胞数目明显减少,折光性差。MTT检测显示实验组抑制率明显高于对照组和空质粒组。实验组的STAT3及其下游靶基因CyclnD1和Bcl-2的mRNA及蛋白的表达明显低于对照组。二、建立大鼠颈静脉移植模型,将其分为2组,对照组和实验组;并应用生物蛋白胶将质粒-脂质体混合物均匀的涂布于移植血管外膜。对照组血管内膜在术后明显增生,而实验组则增生不明显。同时实验组内膜增生的阳性细胞比例明显少于对照组。实验组移植血管STAT3及其下游靶基因CyclnD1和Bcl-2的mRNA及蛋白的表达明显低于对照组。该质粒确实通过对STAT3基因片段的转录翻译过程的抑制作用,阻断了其对下游靶基因CyclinD1和Bcl-2的作用,抑制了VSMCs的增殖,减轻了动脉化静脉壁血管的内膜增生。
Cardiovascular diseases due to atherosclerosis are the main reasons for deaths in the western world. For many patients with severe coronary disease,bypass-surgery is required. Veins are frequently used and have far better results compared with synthetic conduits. But Veins are not ideal bypass conduits which are reflected by the incidence of vein graft failure. Recent studies demonstrated that the primary patency of vein grafts was not better than 60-80 % within the first year after surgery treatment,and by the time when in the tenth year,the failure rate is 50%. A large amount of clinical and experimental studies have demonstrated that intimal thickening may lead to the restenosis of the vein graft. Proliferation and migration of vescular smooth muscle cells(VSMCs) may be a key contributor to neointimal formation. It was demonstrated in a canine vein graft model that the SMCs were transformed from contrictile to a secretory phenotype in response to vessel wall injury. By the switch of phenotypes the SMCs enter a state enabling proliferation,migration,and gain synthetic capacity,which is a pre-requisite for neointimal formation. It has been a well- supported opinion,that the source for the intimal cell population is SMCs from the media. Accumulating evidence sμggests that neointima formation is mediated by a complex interaction of a variety of growth regulatory molecules, such as growth factors,vasoactive peptides,inflammatory cytokines and chemokines.
However,it remains largely unknown which signaling pathways are responsible for neointima formation. STAT3,as one of the candidate signaling pathways,plays an important role in the SMCs proliferation and migration. STAT3 contains a conserved amino-terminal,aDNA-binding domain that binds specific interferon-activated DNA sequences,a SH-2 domain for receptor recruitment and STAT dimerization,and a transactivation domain. STAT3 protein is activated by a variety of stimuli. It is also involved in contradictory responses such as proliferation and apoptosis. Following activation,STAT3 protein changes conformation,forms homo- or hetero-dimers,and translocated from the cytoplasm to the nucleus. In the nucleus,STAT3 binds cis elements,which induce growth responsive and inflammatory genes; including junB,IRF-1,CyclinD1 and anti-apoptotic factors Bcl-xL and Bcl-2. In cultured rat SMCs , the STAT3 activation is substantially involved in the angiotensin II(AII)-or platelet-derived growth factor (PDGF)–induced proliferation.
To prevent restenosis of vein graft,extensive research has been conducted including standard technique of vein harvest and drug therapy et al,but these methods were not an ideal therapy. Two decades ago,gene therapy emerged since the first description of the site-directed transfer of exogenous genetic material into the vascular system .In initial experiments,vascular gene transfer were used to evaluate hypothesis by targeted overex- pression of selected proteins in the vasculature.Therefore,gene therapy as a potential strategy for the treatment of restenosis after angioplasty and vascular bypass graft has been extensively studied. Although effective delivery tools are remain to be solved,these reports sparked the anticipation that such approaches would be used for the therapeutic modulation of vascular responses,including stenosis after injury and restenosis.
In this study,the potential anti-proliferation effects of the recombinant plasmid- Psilencer1.0-U6-siRNA-STAT-3 on VSMCs in vitro and in vivo were investigated to find potential novel strategies for the treatment of restenosis after vein grafting. This plasmid is constructed by RNAi technique to aim at inhibiting mRNA expression and phosphorylation of STAT3. Following this process,Psilencer1.0-U6-siRNA-STAT-3 block the tranicription and translation of the downstream target genes-CyclnD1 and Bcl-2. By this mechanism,proliferation of VSMCs and the neointima formation are inhibited,and restenosis of transpl- anted vein graft is lessen or even blocked. Our study afford a theory base for anti-restenosis after coronary artery bypass graft on clinic.
Psilencer1.0-U6-siRNA-STAT-3 inhibited the proliferation of rat vascular smooth muscle cells in vitro
Methods:RSMCs (2×105 cells per well) seeded in 6-well culture plates were divided into 3 groups: the control group that no transfection were done; the scramble plasmid group in which the scramble plasmid transfected RSMCs and recombinant plasmid group in which RSMCs were transfected with Psilencer1.0-U6-siRNA-STAT-3. The lipofectamine 2000,as the vector,was mixed with plasmid (recombinant plasmid group or scramble)or itself at a proportionality of 0.5μl:0.2μg and added to the RSMCs .After coincubation for 72h,we use contrast phase microscope to observe the shape change of RSMCs; we added MTT solution (5 mg/mL in phosphate-buffered saline (PBS) to observe the proliferation capability of RSMCs; RT-PCR were examined to observe the mRNA expression of STAT3 and its downstream target gene CyclnD1 and Bcl-2; Western-blot were performed to observe expression of their fuctional products-protein.
Results:Observed with contrast phase microscope,Most RSMCs of the control group and scramble plasmid group are clostridial、anomalous triangle or fan shape with clear and intermediate nucleis and proliferate vigorous;however,RSMCs of Psilencer1.0-U6-siRNA- STAT3 group lost their intrinsical form and proliferated slowly with a pycnosis nucleis and some of them even floated in the culture bottle. By MTT assays,the proliferation of RSMCs in Psilencer1.0-U6-siRNA-STAT-3 group was significantly inhibited compared with the control group. RT-PCR detection show significantly decreased mRNA expression of STAT3、CyclnD1 and Bcl-2 in the Psilencer1.0-U6-siRNA-STAT-3 group,whereas the mRNA exepression of them were indistinguishable between the control and scramble plasmid group. Western-blot detection show that STAT3、Bcl-2 and CyclinD1 phosphorylation in the Psilencer1.0-U6-siRNA-STAT-3 group significantly declined compared with those of the control group.
Psilencer1.0-U6-siRNA-STAT-3 inhibited the proliferation of vascular smooth muscle cells in vivo
Methods:we constructed vein graft model and the Psilencer1.0-U6- siRNA- STAT-3/ lipofectamine2000 mixture were mixed with bioprotain gel (volume 80 ul) and sprayed to adventitia of vein graft. 168 free male wistar rats (250-350g) were divided into two groups: the control group (n=84) and recombinant plasmid(experiment)group (n = 84). On day 3、7、14 and 28 after operative procedure,the rats were killed. 5 of these interposed vein graft containing an adjacent section of the left carotid artery were harvested for morphological examination(HE) and immuno- histochemistry(PCNA); 8 of these interposed vein graft were harvested for RT-PCR detection and 8 for Western-blot assay.
Results:The intimal thickening on 3d post operative procedure had not much difference in the two groups,and it peaked on day 7 in the scramble plasmid group,while that in the recombinant plasmid group on day 7 had only scabrosity,on day 14 and 28,it had even no thickening in the experiment group. The thickness of intima had significant difference on day 7(12.3±0.21 and 6.7±0.25 respectively) and 14(7.2±0.31 and 4.6±0.14 respectively); PCNA index in the control group on day 7 and 14 were 31.3±4.7 and 27.2±5.7 respectively and that of experiment group were 23.3±2.8 and 15.6±0.4 respectively; there are significant deviation between the control and experiment group on day 7 and 14 of PCNA positive cells. RT-PCR detection shows that from day 3 after operative procedure,mRNA exepression of STAT3 and its downstream target gene CyclnD1 and Bcl-2 were showed in both the control and exeperiment group,and all peaked at 14d and declined to insignificant level at 28d. Compared with those of the control group,the mRNA expression of the experiment group on 7d decreased significantly. Immunoblotting studies showed that a transient STAT3 induction was accompanied with constitutive expression in the control group,The constitutive STAT3 phosphorylation was detected in the arterialized vein graft after day 3,peaked at day 7,and declined to insignificant levels at day 14. while in the experiment group,although STAT3 phosphorylation detected on day 3 was nearly the same as that in the control group,it was far lower than that of the control group on the 7d; and also that on day 7,CyclnD1 and Bcl-2 proteins level in the experiment group declined significantly compared with that of the control group.
引文
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