Nur77调节PCI术后再狭窄血管平滑肌细胞增殖机制研究
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摘要
目的：建立颈动脉再狭窄大鼠动物模型,探索再狭窄的发病机制并进行干预性研究。
方法：取颈部正中切口,无菌暴露鼠颈动脉；在颈内动脉(ICA)起始部及颈总动脉(CCA)近心侧距动脉分叉2cm处用动脉夹临时夹闭；自颈外动脉(ECA)远端结扎并由结扎近心侧穿刺进入导丝、球囊导管,撤除CCA动脉夹进行球囊扩张血管成形术(PTA)。术后随机分为两组,一组用阿托伐他汀干预,一组作为对照组,于PTA后不同时间进行组织学及形态学分析(左侧颈总动脉作正常对照组)。观察两组内膜厚度与管腔面积。
结果：PTA后早期CCA主要病理改变是血栓形成,中晚期为血管平滑肌细胞(VSMC)由中层移行至内膜并失控增殖伴有基质增多；两组管腔明显狭窄(P<0.01),内膜增厚(P<0.01),药物干预组与对照组相比内膜变薄,管腔面积增加(P<0.05)
结论：大鼠颈总动脉PTA模型模拟了临床过程,成功率高,为PTA之动脉阶段局部用药或转基因治疗实验首选模型。阿托伐他汀减轻球囊扩张术后再狭窄。
目的：观察阿托伐他汀对大鼠血管球囊损伤术后再狭窄中核孤儿受体Nur77表达水平的影响及其与血管平滑肌细胞(VSMCs)增殖的关系,探讨阿托伐他汀防治血管球囊损伤术后再狭窄新的作用机制。
方法：100只SD雄性大鼠高脂饮食,喂养1周后随机分为三组：空白对照组(BC组),血管球囊损伤术组(CG组),血管球囊损伤术后药物组(AIG组)。显微镜下检测各组血管病理形态学改变及平滑肌细胞增殖率,应用免疫组织化学法及Western Blot:分析各组血管组织中Nur77的表达;RT-PCR检测各组血管组织中ERK、PDGF-B、Nur77、NF-κB的基因表达。体外培养VSMCs应用Western Blot分析阿托伐他汀对VSMCs中PDGF-B诱导的Nur77的基因表达。
结果：大鼠血管球囊损伤术后CG组核孤儿受体Nur77表达水平增高,血管内膜-中膜显著增厚(P<0.01)；AIG组血管组织中Nur77表达较BC组增加,较CG组减少,血管内膜-中膜厚度与CG组比较变薄(P<0.05)。PDGF-B诱导VSMCs中Nur77高表达,阿托伐他汀抑制VSMCs中PDGF-B诱导的Nur77蛋白表达。
结论：血管球囊损伤术后,鼠颈动脉内膜增厚,Nur77高表达,血管平滑肌细胞增殖；阿托伐他汀降低损伤血管Nur77表达,抑制血管平滑肌细胞的增殖。体外培养血管平滑肌细胞,阿托伐他汀显著抑制PDGF-B诱导的Nur77表达。通过降低Nur77表达抑制VSMCs增殖,可能是他汀类药物新的预防血管损伤术后再狭窄的机制。
目的：研究PDGF诱导血管平滑肌细胞中Nur77表达机制及其与血管平滑肌细胞增殖的关系。探讨阿托伐他汀对PDGF诱导的血管平滑肌细胞增殖和Nur77表达的关系。
方法：分离培养鼠血管平滑肌细胞,分别与PD98059,阿托伐他汀,siRNANur77孵育后应用PDGF刺激,检测Nur77,ERK表达；检测PCNA表达。
结果：PDGF诱导的血管平滑肌细胞中Nur77通过ERK-MAPK信号途径表达。阿托伐他汀减少PDGF诱导的Nur77表达,抑制血管平滑肌细胞增殖。在Nur77沉默后的血管平滑肌细胞中,PDGF诱导的细胞增殖减少。
结论：PDGF诱导的血管平滑肌细胞增殖受Nur77调控,阿托伐他汀降低Nur77表达减少血管平滑肌细胞增殖,这可能是他汀类药物抗细胞增殖的新的途径。Nur77可能是减少再狭窄的新的治疗靶点。
Objective:To study the mechanism of restenosis for the prevention and treatment by PTA(percutaneous transcather angioplasty)through establishing an model.
Methods:Under median cervical incision, to eploreou mouse carotid artery and then clip the segments of ICA at the origination and CCA near the cardiac side of bifucation, balloon catheter with guided wire were finally inserted from proximal cardiac side of the ligated EC A to perform TA after withdrawing the clipper. Histological and morphological analys-is with the control of normal left CCA were carried out during different follow up periods. And we investigated the effects of atorvastatin on the modle.
Results:Histopathological and morphometric analysis indicating thro-mlmsis was the main changes in early stage and followed by VSMC from media to intima and irregular proliferation leading to obviously intimal thicking and restenosis.Atorvastatin decended the media thickness and area ratios (P<0.05)
Conclusions:This experimental study show low mortality, high pra-cticability and good reproducibility of the model as an ideal presentation for study the mechanism and the prevention of restenosis.
Objective:To investigate the effects of atorvastatin on the expression of Nur77 which is overexpressed in arteriosclerosis lesion and has pro- or anti-proliferative effects on vascular smooth muscle cells (VSMCs).
Methods:By using rat carotid artery postangioplasty restenosis models, we investigated the effects of atorvastatin on the expression of Nur77 by immunohistochemistry, RT-PCR, and Western blot.
Results:Nur77 was up-regulated in neointima, but down-regulated by atorvastatin in rat carotid artery postangioplasty restenosis models.
Conclusions:Down-regulation of Nur77 by atorvastatin suggests a novel therapy strategy for atherogenesis based on suppression of VSMCs proliferation.
Objective:To investigate the expression of PDGF-induced Nur77 mechanism and relationship with proliferation of vascular smooth muscle cells.
Methods:Isolated and cultured VSMC.The expression of Nur77,ERK, PCNA induced by PDGF were checked after incubation with PD98059, atorvastatin, Nur77siRNA respectively.
Results:PDGF-B induced the expression of Nur77 in VSMC through ERK-MAPK signaling pathway.Atorvastatin effected the PDGF-induced Nur77 expression. VSMC proliferation is attenuated in Nur77-deficient cells.
Conclusions:Nur77 regulated VSMC proliferation induced by PDGF. Atorvastatin enduced VSMC proliferation by effecting the expression of Nur77.This may be a new mechanism by which statins affected NF-kB activity by regulating the Nur77 expression.Down-regulation of Nur77 suggests a novel therapy strategy for atherogenesis based on suppression of VSMC proliferation.
方法：取颈部正中切口,无菌暴露鼠颈动脉；在颈内动脉(ICA)起始部及颈总动脉(CCA)近心侧距动脉分叉2cm处用动脉夹临时夹闭；自颈外动脉(ECA)远端结扎并由结扎近心侧穿刺进入导丝、球囊导管,撤除CCA动脉夹进行球囊扩张血管成形术(PTA)。术后随机分为两组,一组用阿托伐他汀干预,一组作为对照组,于PTA后不同时间进行组织学及形态学分析(左侧颈总动脉作正常对照组)。观察两组内膜厚度与管腔面积。
结果：PTA后早期CCA主要病理改变是血栓形成,中晚期为血管平滑肌细胞(VSMC)由中层移行至内膜并失控增殖伴有基质增多；两组管腔明显狭窄(P<0.01),内膜增厚(P<0.01),药物干预组与对照组相比内膜变薄,管腔面积增加(P<0.05)
结论：大鼠颈总动脉PTA模型模拟了临床过程,成功率高,为PTA之动脉阶段局部用药或转基因治疗实验首选模型。阿托伐他汀减轻球囊扩张术后再狭窄。
目的：观察阿托伐他汀对大鼠血管球囊损伤术后再狭窄中核孤儿受体Nur77表达水平的影响及其与血管平滑肌细胞(VSMCs)增殖的关系,探讨阿托伐他汀防治血管球囊损伤术后再狭窄新的作用机制。
方法：100只SD雄性大鼠高脂饮食,喂养1周后随机分为三组：空白对照组(BC组),血管球囊损伤术组(CG组),血管球囊损伤术后药物组(AIG组)。显微镜下检测各组血管病理形态学改变及平滑肌细胞增殖率,应用免疫组织化学法及Western Blot:分析各组血管组织中Nur77的表达;RT-PCR检测各组血管组织中ERK、PDGF-B、Nur77、NF-κB的基因表达。体外培养VSMCs应用Western Blot分析阿托伐他汀对VSMCs中PDGF-B诱导的Nur77的基因表达。
结果：大鼠血管球囊损伤术后CG组核孤儿受体Nur77表达水平增高,血管内膜-中膜显著增厚(P<0.01)；AIG组血管组织中Nur77表达较BC组增加,较CG组减少,血管内膜-中膜厚度与CG组比较变薄(P<0.05)。PDGF-B诱导VSMCs中Nur77高表达,阿托伐他汀抑制VSMCs中PDGF-B诱导的Nur77蛋白表达。
结论：血管球囊损伤术后,鼠颈动脉内膜增厚,Nur77高表达,血管平滑肌细胞增殖；阿托伐他汀降低损伤血管Nur77表达,抑制血管平滑肌细胞的增殖。体外培养血管平滑肌细胞,阿托伐他汀显著抑制PDGF-B诱导的Nur77表达。通过降低Nur77表达抑制VSMCs增殖,可能是他汀类药物新的预防血管损伤术后再狭窄的机制。
目的：研究PDGF诱导血管平滑肌细胞中Nur77表达机制及其与血管平滑肌细胞增殖的关系。探讨阿托伐他汀对PDGF诱导的血管平滑肌细胞增殖和Nur77表达的关系。
方法：分离培养鼠血管平滑肌细胞,分别与PD98059,阿托伐他汀,siRNANur77孵育后应用PDGF刺激,检测Nur77,ERK表达；检测PCNA表达。
结果：PDGF诱导的血管平滑肌细胞中Nur77通过ERK-MAPK信号途径表达。阿托伐他汀减少PDGF诱导的Nur77表达,抑制血管平滑肌细胞增殖。在Nur77沉默后的血管平滑肌细胞中,PDGF诱导的细胞增殖减少。
结论：PDGF诱导的血管平滑肌细胞增殖受Nur77调控,阿托伐他汀降低Nur77表达减少血管平滑肌细胞增殖,这可能是他汀类药物抗细胞增殖的新的途径。Nur77可能是减少再狭窄的新的治疗靶点。
Objective:To study the mechanism of restenosis for the prevention and treatment by PTA(percutaneous transcather angioplasty)through establishing an model.
Methods:Under median cervical incision, to eploreou mouse carotid artery and then clip the segments of ICA at the origination and CCA near the cardiac side of bifucation, balloon catheter with guided wire were finally inserted from proximal cardiac side of the ligated EC A to perform TA after withdrawing the clipper. Histological and morphological analys-is with the control of normal left CCA were carried out during different follow up periods. And we investigated the effects of atorvastatin on the modle.
Results:Histopathological and morphometric analysis indicating thro-mlmsis was the main changes in early stage and followed by VSMC from media to intima and irregular proliferation leading to obviously intimal thicking and restenosis.Atorvastatin decended the media thickness and area ratios (P<0.05)
Conclusions:This experimental study show low mortality, high pra-cticability and good reproducibility of the model as an ideal presentation for study the mechanism and the prevention of restenosis.
Objective:To investigate the effects of atorvastatin on the expression of Nur77 which is overexpressed in arteriosclerosis lesion and has pro- or anti-proliferative effects on vascular smooth muscle cells (VSMCs).
Methods:By using rat carotid artery postangioplasty restenosis models, we investigated the effects of atorvastatin on the expression of Nur77 by immunohistochemistry, RT-PCR, and Western blot.
Results:Nur77 was up-regulated in neointima, but down-regulated by atorvastatin in rat carotid artery postangioplasty restenosis models.
Conclusions:Down-regulation of Nur77 by atorvastatin suggests a novel therapy strategy for atherogenesis based on suppression of VSMCs proliferation.
Objective:To investigate the expression of PDGF-induced Nur77 mechanism and relationship with proliferation of vascular smooth muscle cells.
Methods:Isolated and cultured VSMC.The expression of Nur77,ERK, PCNA induced by PDGF were checked after incubation with PD98059, atorvastatin, Nur77siRNA respectively.
Results:PDGF-B induced the expression of Nur77 in VSMC through ERK-MAPK signaling pathway.Atorvastatin effected the PDGF-induced Nur77 expression. VSMC proliferation is attenuated in Nur77-deficient cells.
Conclusions:Nur77 regulated VSMC proliferation induced by PDGF. Atorvastatin enduced VSMC proliferation by effecting the expression of Nur77.This may be a new mechanism by which statins affected NF-kB activity by regulating the Nur77 expression.Down-regulation of Nur77 suggests a novel therapy strategy for atherogenesis based on suppression of VSMC proliferation.
引文
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