人参皂苷Rb1抑制自体静脉移植物内膜平滑肌细胞增生的研究
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摘要
背景与目的
冠脉动脉旁路移植术是治疗冠状动脉粥样硬化性心脏病(Coronary Atherosclerotic Heart Disease,简称冠心病)的主要方法之一,自从Favaloro[1]首次将大隐静脉应用于冠状动脉旁路移植术以来,大隐静脉由于具有来源丰富,口径较大,易于吻合,取材容易且长度充分等特点,成为临床上主要的移植材料。但种种原因造成的移植静脉再狭窄或闭塞,使移植血管桥的使用寿命受到了一定的限制,远期疗效并不理想。一般来说远期通畅率1年约为80%,5年约为75%,以后每年的闭塞率为2-4%,10年约为50%,所以有一部分人需要接受二次手术。预防移植静脉再狭窄或闭塞成为了研究热点。人参皂苷Rbl是从人参中提取的单体化合物,是一种钙通道阻滞剂,有明显的阻滞ICa2+电流的作用,并且能明显抑制MCT(野百合碱)诱导的RVH(右心室肥大),具有抗心律失常的作用,还具有显著的抗血管内皮缺氧损伤、抗氧自由基等作用,有报道称：人参皂苷Rb1可通过减少内膜增生过程中增殖细胞核抗原(Proliferating Cell Nuclear Antigen,简称PCNA)及转化生长因子-β(Transforming Growth Factor-p,简称TGF-β)的基因表达进而抑制血管平滑肌细胞(vascular smooth muscle cells,简称VSMCs)的过度增殖,减少细胞外基质的形成和分泌,起到抑制内膜过度增生、减轻移植血管再狭窄的作用,延长移植静脉的使用寿命。本实验在建立兔颈外静脉-颈总动脉移植血管桥动物模型的基础上,通过腹腔注射一定剂量的人参皂苷Rb1成品,观察各组移植静脉内膜厚度和形态的变化以及PCNA与TGF-β基因表达的变化,探讨人参皂苷Rbl对移植静脉桥再狭窄或闭塞的抑制作用及其作用机理,为以后的临床应用提供实验基础和理论依据。
材料与方法
45只健康纯种新西兰大白兔,雌雄不限,随机分为实验组、模型组、对照组3组,每组15只。应用"no-touch"外科技术获取右侧颈外静脉后,离断右侧颈总动脉,采用外翻连续缝合方法端端吻合颈外静脉和颈总动脉,建立颈外静脉和颈总动脉旁路移植的动物模型。4周后,取出移植静脉血管,利用HE染色观察移植静脉血管内膜形态和厚度变化,并测量内膜厚度,计算内膜/中膜的厚度比,免疫组化观察静脉移植血管增殖细胞核抗原与转化生长因子-β阳性表达情况,RT-PCR检测移植静脉血管中PCNA及TGF-β mRNA的表达。
结果
1移植静脉HE染色结果
石蜡切片HE染色光镜下观察分析结果显示：移植4周后实验组、模型组的移植静脉内膜均有不同程度的增生重构,模型组更显著,实验组、模型组、对照组移植血管的内膜厚度分别为(41.57±2.43)μm、(73.76±7.83)μm、(11.38±0.71)gm,各组间比较P<0.05,有显著差异。三组移植静脉内膜/中膜厚度比分别为(1.21±0.09)、(1.44±0.12)、(0.28±0.07),各组间比较P<0.05,有显著差异。
2移植静脉免疫组化染色结果观察
移植4周后实验组、模型组、对照组的移植静脉内膜中均可见到PCNA、 TGF-β阳性细胞表达。实验组、模型组、对照组PCNA阳性表达指数分别是(35.24±2.31)%、(57.84±2.79)%、(14.37±1.20)%,各组间比较P<0.05；有显著差异；移植4周后实验组、模型组、对照组TGF-β阳性表达指数分别是(30.28±1.69)%、(52.43±3.85)%、(13.57±1.13)%,各组间比较P<0.05,有明显差异。
3移植静脉RT-PCR结果观察
RT-PCR结果显示各组移植静脉血管中均可见PCNA及TGF-pmRNA表达,但经人参皂苷Rb1干预后,模型组PCNA及TGF-βmRNA相对表达含量明显高于实验组和对照组,以目的基因与内参基因的积分光密度比值计算PCNA及TGF-p的相对含量；移植4周后的实验组、模型组、对照组PCNAmRNA相对含量比值分别是(0.942±0.004)、(0.756±0.003)、(0.574±0.002),各组间比较P<0.05,有显著差异；TGF-βmRNA的相对含量比值分别是(0.921±0.006)、(0.716±0.003)、(0.539±0.004),各组间比较P<0.05,有显著差异。
4相关性分析结果
SPSS简单线性模型结果显示：
(1) PCNA与移植静脉再狭窄呈正相关,相关系数为0.402。
(2) TGF-β与移植静脉再狭窄呈正相关,相关系数为0.376。
结论
1. PCNA的基因表达与移植静脉再狭窄程度呈正相关。
2. TGF-β的基因表达与移植静脉再狭窄程度呈正相关。
3.人参皂苷Rb1能够抑制移植静脉PCNA与TGF-β基因的过度表达,减轻血管平滑肌细胞的过度增殖,这与其能够减轻移植静脉内膜增生重构的作用有关。
Background and Objective
Coronary artery bypass graft(CABG) is one of the most impritmant treatment of Coronary Atherosclerotic Heart Disease(CAD), the great saphenous vein has many advantages,such as:it has the rich source,full length and can be easily acquired,the most importment it has major diameter which is conducive to suture,Since Favaloro the great saphenous vein as graft material,it has become the major clinical transplant material.But various mechanism cause vein grafts restenosis or occlusion which affecsts the service life of vein grafts and reduces Long-term effect. Generally speaking, the long-term patency rate of vein grafts is about80%after one year,75percent after five years, and50%aftwe10years, the annual occlusion rate is2-4%. So some people have to accept the repeated surgery, and the prevention of vein graft stenosis or occlusion has become a research hotspot. Ginsenoside Rbl is a monomer compound extracted from ginseng, it is a calcium channel blockers which can significantly block ICa2+current and reduce right ventricular hypertrophy(RVH) which caused by monocrataline(MCT), it also can resist arrhythmia and the injury of vein grafts caused by hypoxic. It is reported that:Ginsenoside Rb1can inhibit the hyperplasia of vascular smooth muscle cells (VSMCs) by reduce Proliferating Cell Nuclear Antigen(PCNA) and Transforming Growth Factor-beta,(TGF-β) gene expression inthe process of neointimal hyperplasia, and then reduce the synthesis and secretion of extracellularmatrix(ECM),inhibit intimal hyperplasia and extend the service life of the vein graft.The experiment will Establish the animal model in which the external jugular vein of Rabbit will be cut and be sutured to the ipsilateral carotid artery,then inject doses of Ginsenoside Rb1intra
peritoneally to observe the changes of vein graft intimal thickness and morphology as well as PCNA and TGF-β gene expression in the three groups. Exploring the effect of ginsenoside Rbl on inhibition of restenosis in vein grafts and its mechanism of action, and providing experimental and theoretical basis for the future clinical applications
Materials and Methods
A total of45New Zealand rabbits were randomly divided equally into an experimental group, a model group, and a control group. Endoscopic surgery was utilized to excise their external jugular veins, and then establish an animal model for transplanted vein bridges by anastomosing every unilateral jugular vein end-to-end with the common carotid artery. Removing the vein graft after4weeks, the morphology and thickness of the vein graft intimas were observed under hematoxylin and eosin (HE) staining; the endometrial thickness would be measuredtand the intima/media thickness ratio will be calculated; the PCNA and TGF-(3mRNA expression was also examined using reverse transcription polymerase chain reaction.
Results
1The results observed by HE staining:
The HE-stained sections under light microscopy showed that at4weeks after transplantation, the thickness of vein graft intimas in the experimental group, model group,and the control group were (41.57±2.43) μm,(73.76±7.83) μm,(11.38±0.71) μm, with significant differences among the groups (P<0.05), The intimal/medial thickness ratios of the three groups were (1.21±0.09),(1.44±0.12), and (0.28±0.07), which were significantly different (P<0.05).
2The results observed by immunohistochemical staining
PCNA and TGF-(3positive cells can be found in the experimental group, model group and the control group. The Positive cells index of PCNA in the experimental group, model group, and the control group were (35.24±2.31)(57.84±2.79) and (14.37±1.20), The Positive cells index of TGF-(3in the experimental group, model group,and the control group were (30.28±1.69),(52.43±3.85) and (13.57±1.13), with significant differences among the groups (P<0.05).
3The results observed by RT-PCR:
The RT-PCR results showed that the PCNA and TGF-p mRNA can be found in all the three groups, However,after the intervention of ginsenoside Rbl, the relative expression of PCNA and TGF-β mRNA in the model group was significantly higher than the experimental group and control group.The relative expression coefficients of PCNA and TGF-β were calculated by the ratio of the integrated optical density of the target gene and reference gene. The relative expression coefficients of PCNA mRNA in the experimental group, model group, and control group were (0.942±0.004),(0.756±0.003),and (0.574±0.002), which were significantly different (P<0.05); and the relative expression coefficients of PCNA mRNA in the experimental group, model group, and control group were (0.921±0.006),(0.716±0.003) and (0.539±0.004), with significant differences among the groups (P<0.05).
4The results of correlation analysis
The results of Simple linear model in SPSS showed that:
(1) PCNA was positively correlated with the restenosis of vein graft and the correlation coefficient was0.402.
(2) TGF-P was positively correlated with the restenosis of vein graft and the correlation coefficient was0.376.
Conclusion
1. The expression of PCNA gene was positively correlated with the degree of vein grafts restenosis.
2. The expression of TGF-P gene was positively correlated with the degree of vein grafts restenosis.
3. Ginsenoside Rbl can inhibit the over-expression of PCNA and TGF-β gene in the vein graft, reduce the excessive proliferation of vascular smooth muscle cells,which was correlated with the role of reducing the intimal hyperplasia reconstruction of vein grafts.
冠脉动脉旁路移植术是治疗冠状动脉粥样硬化性心脏病(Coronary Atherosclerotic Heart Disease,简称冠心病)的主要方法之一,自从Favaloro[1]首次将大隐静脉应用于冠状动脉旁路移植术以来,大隐静脉由于具有来源丰富,口径较大,易于吻合,取材容易且长度充分等特点,成为临床上主要的移植材料。但种种原因造成的移植静脉再狭窄或闭塞,使移植血管桥的使用寿命受到了一定的限制,远期疗效并不理想。一般来说远期通畅率1年约为80%,5年约为75%,以后每年的闭塞率为2-4%,10年约为50%,所以有一部分人需要接受二次手术。预防移植静脉再狭窄或闭塞成为了研究热点。人参皂苷Rbl是从人参中提取的单体化合物,是一种钙通道阻滞剂,有明显的阻滞ICa2+电流的作用,并且能明显抑制MCT(野百合碱)诱导的RVH(右心室肥大),具有抗心律失常的作用,还具有显著的抗血管内皮缺氧损伤、抗氧自由基等作用,有报道称：人参皂苷Rb1可通过减少内膜增生过程中增殖细胞核抗原(Proliferating Cell Nuclear Antigen,简称PCNA)及转化生长因子-β(Transforming Growth Factor-p,简称TGF-β)的基因表达进而抑制血管平滑肌细胞(vascular smooth muscle cells,简称VSMCs)的过度增殖,减少细胞外基质的形成和分泌,起到抑制内膜过度增生、减轻移植血管再狭窄的作用,延长移植静脉的使用寿命。本实验在建立兔颈外静脉-颈总动脉移植血管桥动物模型的基础上,通过腹腔注射一定剂量的人参皂苷Rb1成品,观察各组移植静脉内膜厚度和形态的变化以及PCNA与TGF-β基因表达的变化,探讨人参皂苷Rbl对移植静脉桥再狭窄或闭塞的抑制作用及其作用机理,为以后的临床应用提供实验基础和理论依据。
材料与方法
45只健康纯种新西兰大白兔,雌雄不限,随机分为实验组、模型组、对照组3组,每组15只。应用"no-touch"外科技术获取右侧颈外静脉后,离断右侧颈总动脉,采用外翻连续缝合方法端端吻合颈外静脉和颈总动脉,建立颈外静脉和颈总动脉旁路移植的动物模型。4周后,取出移植静脉血管,利用HE染色观察移植静脉血管内膜形态和厚度变化,并测量内膜厚度,计算内膜/中膜的厚度比,免疫组化观察静脉移植血管增殖细胞核抗原与转化生长因子-β阳性表达情况,RT-PCR检测移植静脉血管中PCNA及TGF-β mRNA的表达。
结果
1移植静脉HE染色结果
石蜡切片HE染色光镜下观察分析结果显示：移植4周后实验组、模型组的移植静脉内膜均有不同程度的增生重构,模型组更显著,实验组、模型组、对照组移植血管的内膜厚度分别为(41.57±2.43)μm、(73.76±7.83)μm、(11.38±0.71)gm,各组间比较P<0.05,有显著差异。三组移植静脉内膜/中膜厚度比分别为(1.21±0.09)、(1.44±0.12)、(0.28±0.07),各组间比较P<0.05,有显著差异。
2移植静脉免疫组化染色结果观察
移植4周后实验组、模型组、对照组的移植静脉内膜中均可见到PCNA、 TGF-β阳性细胞表达。实验组、模型组、对照组PCNA阳性表达指数分别是(35.24±2.31)%、(57.84±2.79)%、(14.37±1.20)%,各组间比较P<0.05；有显著差异；移植4周后实验组、模型组、对照组TGF-β阳性表达指数分别是(30.28±1.69)%、(52.43±3.85)%、(13.57±1.13)%,各组间比较P<0.05,有明显差异。
3移植静脉RT-PCR结果观察
RT-PCR结果显示各组移植静脉血管中均可见PCNA及TGF-pmRNA表达,但经人参皂苷Rb1干预后,模型组PCNA及TGF-βmRNA相对表达含量明显高于实验组和对照组,以目的基因与内参基因的积分光密度比值计算PCNA及TGF-p的相对含量；移植4周后的实验组、模型组、对照组PCNAmRNA相对含量比值分别是(0.942±0.004)、(0.756±0.003)、(0.574±0.002),各组间比较P<0.05,有显著差异；TGF-βmRNA的相对含量比值分别是(0.921±0.006)、(0.716±0.003)、(0.539±0.004),各组间比较P<0.05,有显著差异。
4相关性分析结果
SPSS简单线性模型结果显示：
(1) PCNA与移植静脉再狭窄呈正相关,相关系数为0.402。
(2) TGF-β与移植静脉再狭窄呈正相关,相关系数为0.376。
结论
1. PCNA的基因表达与移植静脉再狭窄程度呈正相关。
2. TGF-β的基因表达与移植静脉再狭窄程度呈正相关。
3.人参皂苷Rb1能够抑制移植静脉PCNA与TGF-β基因的过度表达,减轻血管平滑肌细胞的过度增殖,这与其能够减轻移植静脉内膜增生重构的作用有关。
Background and Objective
Coronary artery bypass graft(CABG) is one of the most impritmant treatment of Coronary Atherosclerotic Heart Disease(CAD), the great saphenous vein has many advantages,such as:it has the rich source,full length and can be easily acquired,the most importment it has major diameter which is conducive to suture,Since Favaloro the great saphenous vein as graft material,it has become the major clinical transplant material.But various mechanism cause vein grafts restenosis or occlusion which affecsts the service life of vein grafts and reduces Long-term effect. Generally speaking, the long-term patency rate of vein grafts is about80%after one year,75percent after five years, and50%aftwe10years, the annual occlusion rate is2-4%. So some people have to accept the repeated surgery, and the prevention of vein graft stenosis or occlusion has become a research hotspot. Ginsenoside Rbl is a monomer compound extracted from ginseng, it is a calcium channel blockers which can significantly block ICa2+current and reduce right ventricular hypertrophy(RVH) which caused by monocrataline(MCT), it also can resist arrhythmia and the injury of vein grafts caused by hypoxic. It is reported that:Ginsenoside Rb1can inhibit the hyperplasia of vascular smooth muscle cells (VSMCs) by reduce Proliferating Cell Nuclear Antigen(PCNA) and Transforming Growth Factor-beta,(TGF-β) gene expression inthe process of neointimal hyperplasia, and then reduce the synthesis and secretion of extracellularmatrix(ECM),inhibit intimal hyperplasia and extend the service life of the vein graft.The experiment will Establish the animal model in which the external jugular vein of Rabbit will be cut and be sutured to the ipsilateral carotid artery,then inject doses of Ginsenoside Rb1intra
peritoneally to observe the changes of vein graft intimal thickness and morphology as well as PCNA and TGF-β gene expression in the three groups. Exploring the effect of ginsenoside Rbl on inhibition of restenosis in vein grafts and its mechanism of action, and providing experimental and theoretical basis for the future clinical applications
Materials and Methods
A total of45New Zealand rabbits were randomly divided equally into an experimental group, a model group, and a control group. Endoscopic surgery was utilized to excise their external jugular veins, and then establish an animal model for transplanted vein bridges by anastomosing every unilateral jugular vein end-to-end with the common carotid artery. Removing the vein graft after4weeks, the morphology and thickness of the vein graft intimas were observed under hematoxylin and eosin (HE) staining; the endometrial thickness would be measuredtand the intima/media thickness ratio will be calculated; the PCNA and TGF-(3mRNA expression was also examined using reverse transcription polymerase chain reaction.
Results
1The results observed by HE staining:
The HE-stained sections under light microscopy showed that at4weeks after transplantation, the thickness of vein graft intimas in the experimental group, model group,and the control group were (41.57±2.43) μm,(73.76±7.83) μm,(11.38±0.71) μm, with significant differences among the groups (P<0.05), The intimal/medial thickness ratios of the three groups were (1.21±0.09),(1.44±0.12), and (0.28±0.07), which were significantly different (P<0.05).
2The results observed by immunohistochemical staining
PCNA and TGF-(3positive cells can be found in the experimental group, model group and the control group. The Positive cells index of PCNA in the experimental group, model group, and the control group were (35.24±2.31)(57.84±2.79) and (14.37±1.20), The Positive cells index of TGF-(3in the experimental group, model group,and the control group were (30.28±1.69),(52.43±3.85) and (13.57±1.13), with significant differences among the groups (P<0.05).
3The results observed by RT-PCR:
The RT-PCR results showed that the PCNA and TGF-p mRNA can be found in all the three groups, However,after the intervention of ginsenoside Rbl, the relative expression of PCNA and TGF-β mRNA in the model group was significantly higher than the experimental group and control group.The relative expression coefficients of PCNA and TGF-β were calculated by the ratio of the integrated optical density of the target gene and reference gene. The relative expression coefficients of PCNA mRNA in the experimental group, model group, and control group were (0.942±0.004),(0.756±0.003),and (0.574±0.002), which were significantly different (P<0.05); and the relative expression coefficients of PCNA mRNA in the experimental group, model group, and control group were (0.921±0.006),(0.716±0.003) and (0.539±0.004), with significant differences among the groups (P<0.05).
4The results of correlation analysis
The results of Simple linear model in SPSS showed that:
(1) PCNA was positively correlated with the restenosis of vein graft and the correlation coefficient was0.402.
(2) TGF-P was positively correlated with the restenosis of vein graft and the correlation coefficient was0.376.
Conclusion
1. The expression of PCNA gene was positively correlated with the degree of vein grafts restenosis.
2. The expression of TGF-P gene was positively correlated with the degree of vein grafts restenosis.
3. Ginsenoside Rbl can inhibit the over-expression of PCNA and TGF-β gene in the vein graft, reduce the excessive proliferation of vascular smooth muscle cells,which was correlated with the role of reducing the intimal hyperplasia reconstruction of vein grafts.
引文
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