苦参总碱对血管平滑肌细胞增殖和迁移的影响
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摘要
经皮冠状动脉腔内成形术(Percutaneous Transluminal Coronary Angioplasty,PTCA)是目前治疗冠状动脉粥样硬化性心脏病的主要手段,但术后3～6个月的再狭窄(Restenosis,RS)发生率高达30%～50%,大大限制了它在临床上的应用。因此,再狭窄的防治成为心血管病研究领域中的热点问题。近年来,雷帕霉素和紫杉醇药物涂层支架在防治RS临床试验中取得较好的效果,但仍存在一些不能忽视的问题,因此开发出较雷帕霉素、紫杉醇毒副作用更小,更为安全的支架涂层药物至关重要。
再狭窄的发生是众多因素相互作用的十分复杂的过程,包括内膜损伤,血栓形成,中膜血管平滑肌细胞的迁移、增殖,以及血管重塑等一系列病理变化过程。目前认为支架内再狭窄的机制主要是血管损伤后的血管内膜增生,而血管平滑肌细胞的增殖和迁移是后者主要原因之一。针对这一主要病理环节,本文选取中药制剂苦参提取物——苦参总碱,研究其对血管再狭窄的防治作用。本文通过体外细胞实验,研究苦参总碱对血管平滑肌细胞增殖和迁移的影响,并初步探讨相关作用机制。本文主要研究内容及结果如下:
①苦参总碱对血管平滑肌细胞增殖的影响:在体外通过MTT法检测24h、48h、72h三个时间点上不同浓度苦参总碱对血管平滑肌细胞增殖的影响;考马斯亮兰测定细胞总蛋白含量;采用流式细胞仪分析细胞周期。研究结果表明,与对照组相比,苦参总碱对血管平滑肌细胞增殖具有抑制作用,该作用呈剂量及时间的依赖性;流式细胞术检测结果表明,苦参总碱可以使处于Go/G1期的血管平滑肌细胞百分比增高。
②苦参总碱对血管平滑肌细胞迁移的影响:用流动腔装置检测生理剪切流场下测定不同浓度苦参总碱对平滑肌细胞迁移的影响。研究结果显示,与对照组相比,随着苦参总碱浓度增加体外培养的血管平滑肌细胞迁移距离缩短。
适宜浓度的苦参总碱可明显抑制体外培养的血管平滑肌细胞的增殖,迁移。苦参总碱的上述作用可能是通过阻滞血管平滑肌细胞通过细胞周期中的限制点,使其停滞于G0 / G1期来起作用的。
Percutaneous transluminal coronary angioplasty (PTCA) has become the most common major method to treat coronary atherosclerotic heart disease. However, restenosis (RS) which occurs in 30% to 50% of patients within 3~6 months is an important limitation of clinical application of this method. The prevention and cure of restenosis has become the keen spot in the research of cardiology. Rapamycin and Paclitaxel drug-eluting stent have shown the good effect against restenosis in clinical trial recently, but some adverse events could not be ignored. Therefore, it is much significant to exploit these drugs, which has lower toxicant adverse reaction and more safe than Rapamycin and Paclitaxel.
Restenosis is a complicate process, which contains many pathological changes, including intima injurying, thrombus, migration and proliferation of VSMC and blood vessel remodeling. To aim directly at these processes, Sophora Flavescens Alkaloids was chosen and its preventive and therapeutic effect against RS was investigated in the research. The effect of Sophora Flavescens Alkaloids to migration and proliferation of VSMC, was studied by cell experiment in vitro. The main contents of research and conclusions are as follows:
①The effect to proliferation of VSMC: By using MTT ,the effects of Sophora Flavescens Alkaloids of vascular smooth muscle cells (A7r5) on three different times(24h、48h、72h)on the proliferation were analyzed; after treated with Sophora Flavescens Alkaloids, cell total protein content was measured by coomasie briliant blue; Cell cycle analysis was performed by flow cytometry. The results of research showed that growth of VSMC, which were treated by Sophora Flavescens Alkaloids, could be significantly inhibited and it presented dose-time-dependent effect. detected by flow cytometry, most of VSMC were inhibited to through the restriction point of cell cycle and accumulated in G0/G1 compared with the Control group(P<0.05).
②The effect to migration and proliferation of VSMC: vascular smooth muscle cells (A7r5) were subjected to flow shear stress; The result showed that The migration distance of VSMC was decreased as the concentration of Sophora Flavescens Alkaloids increasing.
Sophora Flavescens Alkaloids can significantly inhibit the vasculars mooth muscle cell proliferation and migration in vitro. To inhibit VSMC through the restriction point of cell cycle, which result in accumulation of VSMC in GO/G1,are likely to the mechanism of its action.
再狭窄的发生是众多因素相互作用的十分复杂的过程,包括内膜损伤,血栓形成,中膜血管平滑肌细胞的迁移、增殖,以及血管重塑等一系列病理变化过程。目前认为支架内再狭窄的机制主要是血管损伤后的血管内膜增生,而血管平滑肌细胞的增殖和迁移是后者主要原因之一。针对这一主要病理环节,本文选取中药制剂苦参提取物——苦参总碱,研究其对血管再狭窄的防治作用。本文通过体外细胞实验,研究苦参总碱对血管平滑肌细胞增殖和迁移的影响,并初步探讨相关作用机制。本文主要研究内容及结果如下:
①苦参总碱对血管平滑肌细胞增殖的影响:在体外通过MTT法检测24h、48h、72h三个时间点上不同浓度苦参总碱对血管平滑肌细胞增殖的影响;考马斯亮兰测定细胞总蛋白含量;采用流式细胞仪分析细胞周期。研究结果表明,与对照组相比,苦参总碱对血管平滑肌细胞增殖具有抑制作用,该作用呈剂量及时间的依赖性;流式细胞术检测结果表明,苦参总碱可以使处于Go/G1期的血管平滑肌细胞百分比增高。
②苦参总碱对血管平滑肌细胞迁移的影响:用流动腔装置检测生理剪切流场下测定不同浓度苦参总碱对平滑肌细胞迁移的影响。研究结果显示,与对照组相比,随着苦参总碱浓度增加体外培养的血管平滑肌细胞迁移距离缩短。
适宜浓度的苦参总碱可明显抑制体外培养的血管平滑肌细胞的增殖,迁移。苦参总碱的上述作用可能是通过阻滞血管平滑肌细胞通过细胞周期中的限制点,使其停滞于G0 / G1期来起作用的。
Percutaneous transluminal coronary angioplasty (PTCA) has become the most common major method to treat coronary atherosclerotic heart disease. However, restenosis (RS) which occurs in 30% to 50% of patients within 3~6 months is an important limitation of clinical application of this method. The prevention and cure of restenosis has become the keen spot in the research of cardiology. Rapamycin and Paclitaxel drug-eluting stent have shown the good effect against restenosis in clinical trial recently, but some adverse events could not be ignored. Therefore, it is much significant to exploit these drugs, which has lower toxicant adverse reaction and more safe than Rapamycin and Paclitaxel.
Restenosis is a complicate process, which contains many pathological changes, including intima injurying, thrombus, migration and proliferation of VSMC and blood vessel remodeling. To aim directly at these processes, Sophora Flavescens Alkaloids was chosen and its preventive and therapeutic effect against RS was investigated in the research. The effect of Sophora Flavescens Alkaloids to migration and proliferation of VSMC, was studied by cell experiment in vitro. The main contents of research and conclusions are as follows:
①The effect to proliferation of VSMC: By using MTT ,the effects of Sophora Flavescens Alkaloids of vascular smooth muscle cells (A7r5) on three different times(24h、48h、72h)on the proliferation were analyzed; after treated with Sophora Flavescens Alkaloids, cell total protein content was measured by coomasie briliant blue; Cell cycle analysis was performed by flow cytometry. The results of research showed that growth of VSMC, which were treated by Sophora Flavescens Alkaloids, could be significantly inhibited and it presented dose-time-dependent effect. detected by flow cytometry, most of VSMC were inhibited to through the restriction point of cell cycle and accumulated in G0/G1 compared with the Control group(P<0.05).
②The effect to migration and proliferation of VSMC: vascular smooth muscle cells (A7r5) were subjected to flow shear stress; The result showed that The migration distance of VSMC was decreased as the concentration of Sophora Flavescens Alkaloids increasing.
Sophora Flavescens Alkaloids can significantly inhibit the vasculars mooth muscle cell proliferation and migration in vitro. To inhibit VSMC through the restriction point of cell cycle, which result in accumulation of VSMC in GO/G1,are likely to the mechanism of its action.
引文
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[2] Nrkol S,Huehns TY,HafflingB.Molecularbiologyandpost-angioplasty restenosis[J].Athero sclerosclerosin,1996,123:17
[3] Horlitz M,Sigwart U,Niebauer J.Fighting restenosis after coromary amgoplasty contemporary and future treatment options[J].Ins J Cardiol,2002,83:199
[4] Meuice T,Vallrt B,Barures C,et al.Role of endothelial cells in testenosis comary angioplasty[J].Fundan Clin Pharmacal,1996,10(3):24
[5] 吴永健, 宋光远, 杨跃进. 冠心病介入治疗中的药物支架(二) [J]. 中国医疗器械信息, 2005, 11(3): 28-55.
[6] Sousa JE, CostaMA, Abizaid A, et al. Four year angiographic and intravascular ultrasound follow up of patients treated with sirolimus eluting stents[J]. Circulation, 2005, 111: 2326-2329.
[7] 张文高, 邵念方, 管昌益等. 中医药防治经皮腔内冠状动脉成形术后再狭窄的现状和思路 [J]. 山东中医药大学学报, 2000, 24(1) : 7.
[8] 司维柯,潘静,陆华等. 苦参碱抑制 HepG2 细胞增殖及其剂量与抑制方式关系的研究[J]. 世界华人消化杂志,2001,9 (2):185.
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