钩藤总碱抗高血压血管重塑、抑制血管平滑肌细胞增殖的研究
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摘要
目的:钩藤总碱抗高血压血管重塑、抑制血管平滑肌细胞增殖的作用及其机制。
方法:①在体实验观察钩藤提取物钩藤总碱对SHR尾动脉血压的影响,观察三级动脉血管光镜和体视学变化,检测SHR胸主动脉血管紧张素Ⅱ,胸主动脉平滑肌细胞内Ca~(2+)变化,以研究钩藤总碱的降压、改善血管重塑及可能的机制②建立培养以血管紧张素Ⅱ诱导增殖的VSMC模型。检测指标及方法:MTT反映细胞DNA合成水平,平滑肌细胞生长曲线观察钩藤总碱对细胞生长的抑制作用,流式细胞仪观察VSMC周期、培养细胞内钙的浓度、c-myc基因表达。
结果:钩藤总碱可以降低SHR尾动脉血压,与模型组相比有非常明显差异(P﹤0.01),模型组大鼠胸主动脉、肾动脉和肠系膜动脉的管壁内膜、中膜和外膜均存在不同程度的增厚现象;胸主动脉、肾动脉和肠系膜动脉中膜厚度/管腔直径的比值明显升高,与正常对照组相比存在非常显著的差异(P﹤0.01)。与模型组比较,钩藤总碱组大鼠胸主动脉、肾动脉和肠系膜动脉中膜厚度/管腔直径的比值均明显降低(P﹤0.05)。同时钩藤总碱降低了SHR血管AngⅡ及平滑肌细胞内Ca~(2+)含量,与模型组有显著差异及非常显著性差异(P﹤0.05、P﹤0.01)。离体培养VSMC AngⅡ诱导增殖组具有明显促进VSMC增殖作用;药物组在12h、24h均可抑制VSMC增殖,与模型组比较差异有显著性、非常显著性(P<0.05、P﹤0.01)。各组进行了VSMC生长曲线的描记,经含药物的培养基干预后,细胞生长曲线下移,钩藤总碱组抑制作用较卡托普利组明显。细胞周期研究发现钩藤总碱组与诱导增殖组相比,G1期增高(P﹤0.05), S期明显降低(P﹤0.01),可见钩藤总碱可以阻断细胞由G0/G1期向DNA合成的S期转化,从而抑制培养VSMC增殖的作用。与AngⅡ诱导增殖组相比,钩藤总碱组VSMC Ca~(2+)表达水平显著降低(P<0.01),与AngⅡ诱导增殖组相比,钩藤总碱组VSMCc-myc蛋白表达水平显著降低(P<0.01),说明钩藤总碱抑制VSMC增殖的作用可能与降低细胞内钙水平及调控病理状态下c-myc基因过度表达有关。
结论:钩藤总碱具有降压和改善血管重塑作用,其降压机制与降低血管局局部AngⅡ和VSMC Ca~(2+)有关;改善血管重塑可能与降压和抑制VSMC增殖有关;抑制VSMC增殖的作用与其降低细胞内钙水平及调控病理状态下c-myc基因过度表达有关。
Abjective:the effects and mechanism of the extract of Uncaria rhymchophylla. Jacks on anti- vascular remodeling and inhibiting the proliferation of vascular smooth muscle.
Methods:(1)It was observed that the effect of extract of Uncaria rhymchophylla.Jacks on the SHR blood pressure,the changes of the 3 level of artery structure under microscope and physiology the level of the angiotesinⅡand calcium ion in the SHR aorta vascular smooth muscle in vivo,so that the mechanism of the total alkaloids of Uncaria rhymchophylla.Jacks of the reducing the SHR blood pressure and improving the vascular remodeling was studied. (2)The model of the proliferation of the cultivated vascular smooth muscle cells induced by angiotesinⅡwas made,the examined index and mothods were used as following: the level of DNA synthesis inspected by MTT, the inhibition of the growth of the vascular smoosth muscle cells examined by the cell growth curve,the growth cycle of the vascular smooth muscle cells and the the level of calcium ions and c-myc gene expression in the cultivated cells observed by flow cyteometric analysis,
Results: the blood pressure of SHR tails could be reduced by total alkaloid of Uncaria rhymchophylla.Jacks, compared with model group ,there was obvious difference (P<0.01). the tunica intima, tunica media and tunica advenitia of the aorta, renal and mesenric artery in the model group rats became thicker to different degrees;the ratio of the the thickness tunica media to diameter of the aorta, renal and mesenric artery was increased significantly,compared with normal control group,there was significant difference(P<0.01).compared with the control group,the ratio of the the thickness todiametre of tunica media of the aorta, renal and mesenric artery in total alkaloids of Uncaria rhymchophylla.Jacks group was decreased significantly(P<0.01).at the same time,the total alkaloids of Uncaria rhymchophylla.Jacks reduced the level of the angiotesinⅡand calcium ions in SHR arterys,there was difference and significant difference,compared with model control group(P<0.05,P<0.01).angiotesinⅡcould promote the proliferation of VSMC obviously ; the medicines could inhibited the proliferation of the VSMC during12h and 24h, in medicine groups ;compared with model group,there were significant and very significant diffrence respectively(P<0.05,P<0.01). VSMC growth curves in each groups were recorded; after the intervening of the media contained medicines,the cell growth curves became lower, the inhibition effect in total alkaloids of Uncaria rhymchophylla.Jacks group was stronger than captopril group.It was found that G1 period became high(P<0.05) and S period became lower(P<0.01) in the total alkaloids of Uncaria rhymchophylla.Jacks group ,and total alkaloids of Uncaria rhymchophylla.Jacks blocked the transform from G0/G1 period to synthesis of DNA period,so that the VSMC proliferation was inhibited.Compared with the proliferation group induced by AngⅡ,the level of Ca~(2+) ions expression in VSMC(static condition) was significantly lower and VSMC c-myc protein expression became lower(P<0.01, P<0.01).that possibaly means that total alkaloids of Uncaria rhymchophylla.Jacks inhibits the proliferation of VSMC through reducing the level of the calcium in the cells and the regulating the over–expression of the c-cym gene in the pathological condition.
Conclusion:: total alkaloids of Uncaria rhymchophylla.Jacks has the function of reducing the blood pressure and improving the vascular remolding .the mechanism of reducing the blood pressure maybe concerns the reduction of the local level of AngⅡand Ca~(2+)in the blood vessel.improving the vascular remolding perhaps conserns the decrease of the lowering the blood pressure and inhibiting the proliferation of the VSMC. The effect of inhibiting the proliferation possibaly conserns reducing the level of the calcium in the cells and the regulating the over–expression of the c-myc gene in the pathological condition.
方法:①在体实验观察钩藤提取物钩藤总碱对SHR尾动脉血压的影响,观察三级动脉血管光镜和体视学变化,检测SHR胸主动脉血管紧张素Ⅱ,胸主动脉平滑肌细胞内Ca~(2+)变化,以研究钩藤总碱的降压、改善血管重塑及可能的机制②建立培养以血管紧张素Ⅱ诱导增殖的VSMC模型。检测指标及方法:MTT反映细胞DNA合成水平,平滑肌细胞生长曲线观察钩藤总碱对细胞生长的抑制作用,流式细胞仪观察VSMC周期、培养细胞内钙的浓度、c-myc基因表达。
结果:钩藤总碱可以降低SHR尾动脉血压,与模型组相比有非常明显差异(P﹤0.01),模型组大鼠胸主动脉、肾动脉和肠系膜动脉的管壁内膜、中膜和外膜均存在不同程度的增厚现象;胸主动脉、肾动脉和肠系膜动脉中膜厚度/管腔直径的比值明显升高,与正常对照组相比存在非常显著的差异(P﹤0.01)。与模型组比较,钩藤总碱组大鼠胸主动脉、肾动脉和肠系膜动脉中膜厚度/管腔直径的比值均明显降低(P﹤0.05)。同时钩藤总碱降低了SHR血管AngⅡ及平滑肌细胞内Ca~(2+)含量,与模型组有显著差异及非常显著性差异(P﹤0.05、P﹤0.01)。离体培养VSMC AngⅡ诱导增殖组具有明显促进VSMC增殖作用;药物组在12h、24h均可抑制VSMC增殖,与模型组比较差异有显著性、非常显著性(P<0.05、P﹤0.01)。各组进行了VSMC生长曲线的描记,经含药物的培养基干预后,细胞生长曲线下移,钩藤总碱组抑制作用较卡托普利组明显。细胞周期研究发现钩藤总碱组与诱导增殖组相比,G1期增高(P﹤0.05), S期明显降低(P﹤0.01),可见钩藤总碱可以阻断细胞由G0/G1期向DNA合成的S期转化,从而抑制培养VSMC增殖的作用。与AngⅡ诱导增殖组相比,钩藤总碱组VSMC Ca~(2+)表达水平显著降低(P<0.01),与AngⅡ诱导增殖组相比,钩藤总碱组VSMCc-myc蛋白表达水平显著降低(P<0.01),说明钩藤总碱抑制VSMC增殖的作用可能与降低细胞内钙水平及调控病理状态下c-myc基因过度表达有关。
结论:钩藤总碱具有降压和改善血管重塑作用,其降压机制与降低血管局局部AngⅡ和VSMC Ca~(2+)有关;改善血管重塑可能与降压和抑制VSMC增殖有关;抑制VSMC增殖的作用与其降低细胞内钙水平及调控病理状态下c-myc基因过度表达有关。
Abjective:the effects and mechanism of the extract of Uncaria rhymchophylla. Jacks on anti- vascular remodeling and inhibiting the proliferation of vascular smooth muscle.
Methods:(1)It was observed that the effect of extract of Uncaria rhymchophylla.Jacks on the SHR blood pressure,the changes of the 3 level of artery structure under microscope and physiology the level of the angiotesinⅡand calcium ion in the SHR aorta vascular smooth muscle in vivo,so that the mechanism of the total alkaloids of Uncaria rhymchophylla.Jacks of the reducing the SHR blood pressure and improving the vascular remodeling was studied. (2)The model of the proliferation of the cultivated vascular smooth muscle cells induced by angiotesinⅡwas made,the examined index and mothods were used as following: the level of DNA synthesis inspected by MTT, the inhibition of the growth of the vascular smoosth muscle cells examined by the cell growth curve,the growth cycle of the vascular smooth muscle cells and the the level of calcium ions and c-myc gene expression in the cultivated cells observed by flow cyteometric analysis,
Results: the blood pressure of SHR tails could be reduced by total alkaloid of Uncaria rhymchophylla.Jacks, compared with model group ,there was obvious difference (P<0.01). the tunica intima, tunica media and tunica advenitia of the aorta, renal and mesenric artery in the model group rats became thicker to different degrees;the ratio of the the thickness tunica media to diameter of the aorta, renal and mesenric artery was increased significantly,compared with normal control group,there was significant difference(P<0.01).compared with the control group,the ratio of the the thickness todiametre of tunica media of the aorta, renal and mesenric artery in total alkaloids of Uncaria rhymchophylla.Jacks group was decreased significantly(P<0.01).at the same time,the total alkaloids of Uncaria rhymchophylla.Jacks reduced the level of the angiotesinⅡand calcium ions in SHR arterys,there was difference and significant difference,compared with model control group(P<0.05,P<0.01).angiotesinⅡcould promote the proliferation of VSMC obviously ; the medicines could inhibited the proliferation of the VSMC during12h and 24h, in medicine groups ;compared with model group,there were significant and very significant diffrence respectively(P<0.05,P<0.01). VSMC growth curves in each groups were recorded; after the intervening of the media contained medicines,the cell growth curves became lower, the inhibition effect in total alkaloids of Uncaria rhymchophylla.Jacks group was stronger than captopril group.It was found that G1 period became high(P<0.05) and S period became lower(P<0.01) in the total alkaloids of Uncaria rhymchophylla.Jacks group ,and total alkaloids of Uncaria rhymchophylla.Jacks blocked the transform from G0/G1 period to synthesis of DNA period,so that the VSMC proliferation was inhibited.Compared with the proliferation group induced by AngⅡ,the level of Ca~(2+) ions expression in VSMC(static condition) was significantly lower and VSMC c-myc protein expression became lower(P<0.01, P<0.01).that possibaly means that total alkaloids of Uncaria rhymchophylla.Jacks inhibits the proliferation of VSMC through reducing the level of the calcium in the cells and the regulating the over–expression of the c-cym gene in the pathological condition.
Conclusion:: total alkaloids of Uncaria rhymchophylla.Jacks has the function of reducing the blood pressure and improving the vascular remolding .the mechanism of reducing the blood pressure maybe concerns the reduction of the local level of AngⅡand Ca~(2+)in the blood vessel.improving the vascular remolding perhaps conserns the decrease of the lowering the blood pressure and inhibiting the proliferation of the VSMC. The effect of inhibiting the proliferation possibaly conserns reducing the level of the calcium in the cells and the regulating the over–expression of the c-myc gene in the pathological condition.
引文
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