钩藤总碱抑制高血压血管外膜重构的机制研究
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摘要
目的:探讨钩藤总碱抑制高血压血管外膜重构的机制。
方法:以培养Wistar大鼠血管成纤维细胞为研究平台,通过血管紧张素Ⅱ(AngⅡ)体外干预血管外膜成纤维细胞建立高血压外膜重构模型;观察钩藤总碱的细胞毒性,从而选用合适的实验药物浓度(MTT);利用电子显微镜更加直观的反映钩藤总碱对血管紧张素Ⅱ诱导增殖的成纤维细胞形态的影响;通过与卡托普利组和AngⅡ诱导增殖模型组比较,利用流式细胞仪,研究钩藤总碱对血管成纤维细胞细胞周期的影响;采用RT-PCR法检测血管外膜成纤维细胞Ⅰ、Ⅲ型胶原mRNA的表达,从基因表达水平研究钩藤总碱对血管成纤维细胞中胶原合成的调节作用;综合分析钩藤总碱对高血压血管外膜重构的影响。
结果:本实验利用AngⅡ体外干预血管外膜成纤维细胞建立高血压外膜重构模型是成立的;AngⅡ体外干预血管成纤维细胞建立高血压外膜重构模型的最适浓度2×10-7mol/L;卡托普利的药物干预剂量是400ug/ml;钩藤总碱的药物干预剂量是200ug/ml和400ug/ml;电镜下观察钩藤总碱对血管成纤维细胞的增殖有抑制作用,400 ug/ml钩藤总碱干预下的血管成纤维细胞有细胞凋亡的表现;细胞周期的结果提示钩藤总碱对AngⅡ的促VAF增殖效应的抑制作用是通过增加G_0 /G_1期细胞百分含量,减少S期细胞的百分含量,阻断细胞由G_0 /G_1期向S期转化而实现的,并且这种抑制作用与卡托普利比较无明显差异;钩藤总碱可抑制AngⅡ刺激的血管外膜成纤维细胞的Ⅰ、Ⅲ型胶原mRNA的表达;对Ⅰ型胶原mRNA的表达呈剂量依赖性,与卡托普利相比其抑制关系为400ug/ml钩藤总碱>卡托普利,卡托普利和200ug/ml钩藤总碱无明显差异。三组干预药物对Ⅲ型胶原mRNA的表达的抑制作用无明显差异。
结论:钩藤总碱抑制高血压外膜重构的机制有两方面。一方面,钩藤总碱可以抑制血管紧张素Ⅱ诱导的血管外膜成纤维细胞的增殖,其抑制血管外膜成纤维细胞增殖的途径是通过增加G_0 /G_1期细胞百分含量,减少S期细胞的百分含量,阻断细胞由G_0 /G_1期向S期转化而实现的;另一方面钩藤总碱能够减少血管外膜Ⅰ、Ⅲ型胶原的合成,其途径是通过下调血管外膜成纤维细胞Ⅰ、Ⅲ型胶原mRNA的表达实现的。
Objective:To discuss the effects and mechanism of rhynchophylla total alkaloid inhibiting vascular remondeling in adventitia. And the mechanism inhibiting the proliferation of vascular adventitia fibroblast. Methods:Based on vascular adventitia fibroblast culture, we model hypertension vascular remondeling by angiotensionⅡ;Obverving ryhnehophylla total alkaloid cytotoxicity and choosing appropriate drug concentration, we make use of MTT; Using electron microscope, we can visually observe proliferous vascular adventitia fibroblast induced by angiotensionⅡ;Making use of flow cytometry, we can research the variety of vascular adventitia fibroblast’s cell cycle affected by rhynchophylla total alkaloid; We also test the gene expression of collagen typeⅠandⅢ. Results:It is successful for us to model hypertension vascular remondeling by angiotensionⅡ.And the most appropriate concentration for angiotensionⅡis 2×10-7mol/L. 200ug/ml~400ug/ml rhynchophylla total alkaloid inhibiting is the best drug concentration.Rhynchophylla total alkaloid can inhibit the proliferation of vascular adventitia fibroblast from MTT and electron microscope. The results of low cytometry show that rhynchophylla total alkaloid can increase VAF in G_0 /G_1 phase and decrease VAF in S phase. And this inhibition is dependent on drug concentration. Rhynchophylla total alkaloid can inhibit the gene expression of collagen typeⅠandⅢ. Conclusions: Rhynchophylla total alkaloid can inhibit proliferation of vascular adventitia fibroblast. The mechanism of this inhibiting effect probably in two ways. The one is to increase VAF in G0 /G1 phase and decrease VAF in S phase. The other is to inhibit the gene expression of collagen typeⅠandⅢ.So rhynchophylla total alkaloid can inhibit vascular remondeling in adventitia.
方法:以培养Wistar大鼠血管成纤维细胞为研究平台,通过血管紧张素Ⅱ(AngⅡ)体外干预血管外膜成纤维细胞建立高血压外膜重构模型;观察钩藤总碱的细胞毒性,从而选用合适的实验药物浓度(MTT);利用电子显微镜更加直观的反映钩藤总碱对血管紧张素Ⅱ诱导增殖的成纤维细胞形态的影响;通过与卡托普利组和AngⅡ诱导增殖模型组比较,利用流式细胞仪,研究钩藤总碱对血管成纤维细胞细胞周期的影响;采用RT-PCR法检测血管外膜成纤维细胞Ⅰ、Ⅲ型胶原mRNA的表达,从基因表达水平研究钩藤总碱对血管成纤维细胞中胶原合成的调节作用;综合分析钩藤总碱对高血压血管外膜重构的影响。
结果:本实验利用AngⅡ体外干预血管外膜成纤维细胞建立高血压外膜重构模型是成立的;AngⅡ体外干预血管成纤维细胞建立高血压外膜重构模型的最适浓度2×10-7mol/L;卡托普利的药物干预剂量是400ug/ml;钩藤总碱的药物干预剂量是200ug/ml和400ug/ml;电镜下观察钩藤总碱对血管成纤维细胞的增殖有抑制作用,400 ug/ml钩藤总碱干预下的血管成纤维细胞有细胞凋亡的表现;细胞周期的结果提示钩藤总碱对AngⅡ的促VAF增殖效应的抑制作用是通过增加G_0 /G_1期细胞百分含量,减少S期细胞的百分含量,阻断细胞由G_0 /G_1期向S期转化而实现的,并且这种抑制作用与卡托普利比较无明显差异;钩藤总碱可抑制AngⅡ刺激的血管外膜成纤维细胞的Ⅰ、Ⅲ型胶原mRNA的表达;对Ⅰ型胶原mRNA的表达呈剂量依赖性,与卡托普利相比其抑制关系为400ug/ml钩藤总碱>卡托普利,卡托普利和200ug/ml钩藤总碱无明显差异。三组干预药物对Ⅲ型胶原mRNA的表达的抑制作用无明显差异。
结论:钩藤总碱抑制高血压外膜重构的机制有两方面。一方面,钩藤总碱可以抑制血管紧张素Ⅱ诱导的血管外膜成纤维细胞的增殖,其抑制血管外膜成纤维细胞增殖的途径是通过增加G_0 /G_1期细胞百分含量,减少S期细胞的百分含量,阻断细胞由G_0 /G_1期向S期转化而实现的;另一方面钩藤总碱能够减少血管外膜Ⅰ、Ⅲ型胶原的合成,其途径是通过下调血管外膜成纤维细胞Ⅰ、Ⅲ型胶原mRNA的表达实现的。
Objective:To discuss the effects and mechanism of rhynchophylla total alkaloid inhibiting vascular remondeling in adventitia. And the mechanism inhibiting the proliferation of vascular adventitia fibroblast. Methods:Based on vascular adventitia fibroblast culture, we model hypertension vascular remondeling by angiotensionⅡ;Obverving ryhnehophylla total alkaloid cytotoxicity and choosing appropriate drug concentration, we make use of MTT; Using electron microscope, we can visually observe proliferous vascular adventitia fibroblast induced by angiotensionⅡ;Making use of flow cytometry, we can research the variety of vascular adventitia fibroblast’s cell cycle affected by rhynchophylla total alkaloid; We also test the gene expression of collagen typeⅠandⅢ. Results:It is successful for us to model hypertension vascular remondeling by angiotensionⅡ.And the most appropriate concentration for angiotensionⅡis 2×10-7mol/L. 200ug/ml~400ug/ml rhynchophylla total alkaloid inhibiting is the best drug concentration.Rhynchophylla total alkaloid can inhibit the proliferation of vascular adventitia fibroblast from MTT and electron microscope. The results of low cytometry show that rhynchophylla total alkaloid can increase VAF in G_0 /G_1 phase and decrease VAF in S phase. And this inhibition is dependent on drug concentration. Rhynchophylla total alkaloid can inhibit the gene expression of collagen typeⅠandⅢ. Conclusions: Rhynchophylla total alkaloid can inhibit proliferation of vascular adventitia fibroblast. The mechanism of this inhibiting effect probably in two ways. The one is to increase VAF in G0 /G1 phase and decrease VAF in S phase. The other is to inhibit the gene expression of collagen typeⅠandⅢ.So rhynchophylla total alkaloid can inhibit vascular remondeling in adventitia.
引文
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