摘要
第一部分CAPE对培养的血管平滑肌细胞生长的影响
目的:观察不同浓度的咖啡酸苯乙酯(caffeic acid phenethyl ester CAPE)对脂多糖(lipopolyccharide LPS)激活的血管平滑肌细胞(vascular smooth muscle cells, VSMCs)生长情况的影响。
方法: DMEM细胞培养基中加入不同浓度药物为试验组,不加者为对照组。用MTT比色法描述不同浓度LPS作用VSMCs 72h内的生长情况,及CAPE对一定浓度LPS(1mg﹒L-1)激活VSMCs 120h的影响;通过平板克隆实验观察LPS和CAPE作用3周对细胞增殖的影响;细胞免疫化学法用于检测CAPE作用72小时后VSMCs表达PCNA情况。
结果:
1不同浓度LPS对VSMCs生长的影响0.1-10 mg﹒L-1 LPS实验组O.D值较对照组明显升高,表明一定浓度范围内的LPS能增强VSMCs增殖。5.10.20.40.80 mg﹒L-1CAPE作用VSMCs(1mg﹒L-1 LPS刺激)后具有显著抑制细胞的增殖作用,且呈时间和剂量效依赖关系。
2平板克隆实验一定浓度范围的LPS作用于VSMCs3周可明显增加细胞克隆的形成,而CAPE明显抑制细胞克隆的形成。CAPE浓度越高,形成的克隆数就越少;3 CAPE对VSMCs中PCNA蛋白表达的影响PCNA蛋白阳性反应定位在细胞核或核膜,呈棕黄色或棕褐色。VSMCs经0-10 mg﹒L-1 LPS刺激时,各实验组PCNA逐渐增高,与对照组比较有显著差异;经不同浓度CAPE处理后,PCNA阳性率由对照组的91.8%±1.7%逐渐降低为最高CAPE浓度组的40.0%±1.8%(p<0.01)。
4药物溶剂DMSO对VSMCs增殖没有显著影响。
结论:通过MTT试验,细胞克隆形成试验以及PCNA蛋白检测试验,发现LPS作为刺激因子可显著激活VSMCs体外培养时的生长,在一定浓度范围内与LPS的剂量呈以来关系。同时试验还发现作为干预因素,CAPE可显著抑制LPS激活的VSMCs的生长,并与药物的作用时间和剂量相关。试验显示CAPE抑制细胞生长与PCNA阳性表达率降低有关,提示抑制细胞周期相关蛋白的表达可能是其作用机制之一。
第二部分CAPE影响培养的VSMCs生长的机制
目的:探讨不同浓度的CAPE抑制激活的血管平滑肌细胞(vascular smooth muscle cells, VSMCs)生长情况的机制。
方法:采用ELISA法检测细胞培养基上清液中IL-6, TNF-α等细胞因子。流式细胞仪检测CAPE对VSMCs细胞周期的变化和凋亡的影响;采用凝胶迁移或电泳迁移率检测法(electrophoretic mobility shift assays,EMSA)检测核转录因子-κB(nuclear factor of kappa B,NF-κB)在平滑肌细胞中的活性;实时定量PCR技术用于检测细胞中Sur(survivin,存活素),Bcl-2及Bax表达水平的变化。
结果:
1 LPS导致细胞培养液中IL-6,TNF-α皆有升高,并且随着LPS浓度的增加IL-6,TNF-α的浓度升高;同时随着LPS刺激时间的延长,细胞因子的浓度也升高。而CAPE对有一定浓度刺激的VSMCs产生的IL-6,TNF-α有抑制作用,其抑制效果与CAPE的浓度和作用时间有关。
2细胞周期分析表明5-20mg﹒L-1 CAPE处理VSMCs 24 h后,对照组实验组G0/G1期细胞百分率明显升高;S期细胞百分率由对照组的32.4%±2.6%逐渐下降20 mg/L组的11.2%±1.4%,呈剂量依赖性(p<0.05)。
3流式细胞仪发现5-20 mg﹒L-1 CAPE作用VSMCs 24h后,细胞的凋亡率分别为(10.1%±0.7%,18.9%±1.3%,27.3%±2.4%)显著高于对照组(4.2%±0.3%)(P<0.05),且凋亡细胞随CAPE剂量的增加逐渐增多。
4 EMSA实验发现LPS使平滑肌细胞中NF-κB活性增加,而CAPE则可显著抑制其活性。
5不同浓度LPS和CAPE对细胞表达mRNA的影响相反。LPS增加细胞在表达抗凋亡的相关mRNA,同时抑制促进凋亡的相关mRNA表达。而CAPE的作用则相反。CAPE各组细胞表达Bax mRNA水平升高,Sur和Bcl-2 mRNA表达水平与对照组比较明显下降。
结论: CAPE使处于G0/G1期的细胞增加S期的减少同时CAPE促进细胞凋亡;ELISA和EMSA试验表明CAPE对细胞因子的影响;同时CAPE还使细胞表达抗凋亡基因降低,促凋亡基因表达增加。这些证据表明一定剂量范围的CAPE可能是通过调节细胞周期,影响细胞释放细胞因子,干预NF-κB活性以及细胞凋亡相关基因的表达等多个机制和手段抑制体外培养的VSMCs增殖的。
第三部分CAPE对大鼠颈总动脉球囊扩张术后内膜增生的影响及其机制
目的:为探索RS的发病机制并进行干预研究,我们模拟复制大鼠颈总动脉内膜损伤后不同时间点的VSMCs增殖和血管重塑动态变化模型,并探讨CPAE对血管内皮损伤诱发的VSMCs增殖的抑制作用及对活体大鼠表达Sur, Bax, Bcl-2等凋亡相关基因的影响。
方法:建立雄性SD大白鼠(体重300~350g)颈动脉损伤的动物模型,动物随机分为:假损伤组( sham - injured group,S组)、损伤组( injured group,I组)和损伤+ CAPE治疗组( injured +20 mg kg -1CAPE - treated group,CAPE组)。采用HE染色法弹力显微染色法检测3、7、14、28d血管形态学改变,计算机图像分析系统检测新生内膜厚度(H),新生内膜面积(NIA),中膜面积(MA),内弹力板围绕面积(IEM)、外弹力板围绕面积(EEM)、各组血管腔面积(lumen area,LA)并计算新生内膜面积/中膜面积(NIA/MA)、管腔狭窄指数(NIA/IEM);免疫组织化学SABC法检测I组和CAPE组血管壁细胞中Sur、Bax和Bcl-2蛋白的表达,计算机图像分析蛋白表达的平均光密度值。TUNEL法检测细胞凋亡率。ELISA法检测血清中IL-6, TNF-α等细胞因子。EMSA实验用于检测血管壁细胞中NF-κB活性。实时定量PCR检测血管壁Sur,Bax及Bcl-2 mRNA的表达水平。
结果:
1 S组大鼠总动脉内膜仅见单层内皮细胞;I组球囊损伤后3d血管腔内表面可见增殖的VSMCs, 14d内新生内膜(neointima,NI)形成并厚度增加,同时细胞外基质( extracellular matrix,ECM )也逐渐增加。14d时中膜面积明显大于未损伤血管。LA 14d以后明显小于未损伤侧。损伤后3 ~ 7 d NIA/MA,NIA/IEM至14 d达最大。CAPE组各项指标与I组比较有相反的变化趋势。
2 S组血管壁组织细胞中的Sur,Bcl-2和Bax蛋白表达水平相对较低。I组的Sur蛋白水平术后14天内持续升高,在28天时发现其表达水平较第14天降低;Bcl-2蛋白表达水平一直升高;Bax蛋白术后也升高,7d后开始下降。CAPE组Sur,Bcl-2蛋白水平较I组降低,但Bax蛋白较I组升高。
3 S组血管TUNEL染色未见阳性着色;球囊损伤后TUNEL阳性细胞先增多后减少。CAPE使细胞凋亡率增加,其作用随时间的延长而加强。
4 S组术后IL-6和TNF-α逐渐升高。I组细胞因子血清比S组显著升高,与S组相比差异显著(P<0.01); CAPE组术后6h血清TNF-α含量与I组相比显著降低(P<0.01)
5 EMSA实验发现S组血管组织中未见NF-κB活性,I组中NF-κB活性在48h内持续升高,之后开始下降至损伤即可水平而CAPE则可显著抑制其活性。
6实时定量RT-PCR表明S组血管壁组织细胞中的Sur,Bcl-2和Bax mRNA表达水平相对较低。I组中mRNA的变化趋势与其蛋白表达的变化相似。CAPE组Sur,Bcl-2 mRNA水平较I组降低,但Bax mRNA升高明显。
结论: CAPE能显著抑制球囊扩张术后血管内膜增生,其作用效力与药物的作用时间有关。药物的作用机制可能与一定量的CAPE导致细胞生存相关的基因表达发生改变,使Sur,Bcl-2等促使细胞增生的基因表达降低,同时调节Bax等促使细胞凋亡的基因高表达等机制有关;另外,实验还发现CAPE能调节实验动物血清中细胞因子的水平,这也可能是其作用机制之一。
PARTⅠThe Effects of on the growth Dynamics of Vascular Smooth Muscle Cells in vitro
Objective: To observe the effects of caffeic acid phenethyl ester (CAPE) ranged from 5 mg﹒L-1 to 80 mg﹒L-1 on the growth dynamics of vascular smooth muscle cells (VSMCs) stimulated by lipopolysaccharide (LPS)
Methods:LPS or CAPE was added into the medium to treat VSMCs. MTT assay method was used to descript the effects of LPS and CAPE on the growth of the VSMCs in 72h or 120h. Cells were stimulated by 1 mg﹒L-1 LPS when cells were treated by CAPE; Cell clones were counted in plates after cultured for 3 week. Immunocytochemistry(ICC)was utilized to detect the effect of CAPE on the exprssion of proliferating cell nuclear antigen (PCNA) in VSMCs when cells had been cultured for 72h.
Results: 0.1-10 mg﹒L-1 LPS showed a significantly inducible effect on the growth of VSMCs. And CAPE showed an inhibitory effect on the proliferation of VSMCs activated by 1 mg﹒L-1 LPS. The inhibitive curve showed CAPE excerted a significantly inhibitory effect in a dose- and time-dependent manner, especially when the cells had been exposed in culture medium with CAPE for over 72h.
LPS had an opposite effect on the generation of cell clones to CAPE. 0.1-10 mg﹒L-1 LPS can promote VSMCs to emerge clones but CAPE play a part in inhibiting the generation of cell clones. The difference was more remarkable in the higher concentration groups.
While VSMCs were activated by LPS of 0.1-10 mg﹒L-1, the rates of the cells positive for PCNA increased compared with the control. After treated with different concentrations of CAPE, the positive rate for PCNA was decreased from 91.8%±1.7% in the control down to 40.0%±1.8% in the 80 mg﹒L-1 CAPE treated group. Compared with the control, the rates of the cells positive treated with LPS or CAPE were significantly different (p<0.05 or p<0.01). The results also showed that LPS and CAPE both affected the expression of PCNA in a dose-dependent manner.
DSMO had no remarkable effect on the growthof VSMCs
Conclusions: MTT assay, cell clones experiment and ICC for PCNA showed 0.1-10 mg﹒L-1 LPS significantly stimulated the proliferation of VSMCs in a dose-dependent manner. But CAPE ranged from 5-80 mg﹒L-1 inhibited the proliferation of VSMCs stimulated by 1 mg﹒L-1 LPS in a dose- and time- dependent manner. Meanwhile, CAPE of different concentrations decreased the positive rate of PCNA which indicated that it was one of the mechanisms that CAPE inhibited the expression of protein related to cell cycle.
PARTⅡThe Mechanisms of CAPE Inhibiting the Growth of VSMCs Cultured in vitro
Objective:To elucodate the primary mechanisms of CAPE ranged from 5 mg﹒L-1 to 80 mg﹒L-1 which inhibited the growthof VSMCs.
Methods:The changes of IL-6 and TNF-αin the supernatant liquid were determined by Enzyme-linked Immunosorbnent Assay (ELISA). The effect of CAPE on the cell cycle of VSMCs was measured by flow cytometry (FCM) assay and the same method was utilized to detect the apoptosis of VSMCs. Electrophoretic mobility shift assays (EMSA) was used to examine nuclear factor of kappa B (NF-κB) activation in VSMCs. Real-time quantitative PCR method was usded to show the exprssion levels of Sur, Bcl-2 and Bax mRNA.
Results: LPS ranged from 0.1 to10 mg﹒L-1 stimulated VSMCs to generate IL-6 and TNF-αin the supernatant liquid and CAPE ranged from 5 to 80 mg﹒L-1 lowered the levels of IL-6 and TNF-αin a dose- and time-dependent manner.
After cells had been exposed to CAPE (5.10.20 mg﹒L-1) for 24 h, FCM analysis displayed that the rates of cells in G0/G1 stage in the treated groups significantly increased compared with the control and the percentage of S stage were down-regulated(p<0.05). FCM analysis also determined the rate of the apoptosis of VSMCs in the control group(4.2%±0.3%) was significantly less than the treated groups (10.1%±0.7%,18.9%±1.3%,27.3%±2.4%) (p<0.05 or p<0.01).
LPS can up-regulated the expression of Sur mRNA in VSMCs when cells were treated with LPS ranged from 0.1 mg﹒L-1 to 10 mg﹒L-1 ( p<0.05 ). The experiment results also showed that CAPE down-regulated significantly the expression levels of Sur mRNA (p<0.05 or p<0.01). The changing tendency of the expression of Bcl-2 mRNA was similar to Sur but Bax mRNA had the contrary tendency.
LPS enhanced NF-κB avtivity in VSMCs but CAPE inhibited the activation in VSMCs stimulated by 1 LPS mg﹒L-1
Conclusions: Both ELISA and EMSA experiments showed that CAPE lowered VSMCs to serect cytokines and inhibited NF-κB activation in cells. CAPE also regulated the cell cycle, urged the apoptosis of cells and changed the expression levels of Sur, Bcl-2 and Bax mRNA. These indicated that the mechanisms of CAPE impacting VSMCs may be relative to its regulating the cell cycle and the expression of genes of apoptosis. And its inhibitory effect on the serection of cytokine and NF-κB activation also played an important role in inhibiting the growthof VSMCs. So we conclued rhat CAPE had the potential as an effective anti-restenosis therapy after PCI.
PARTⅢPreventive Effects and its Mechanisms of CAPE on Vascular Restennosis Induced by intima Injury after Balloon Lesions
Objective: To study the mechanism of restenosis for the prevention and treatment following percutaneous coronary intervention (PCI), we replicated the dynamic models of cellular proliferation and vascular remodeling after intimal denudation of rats carotid common arteries at different time points and to investigate the effects of CAPE on the proliferation of VSMCs induced by intimal denudation after balloon lesions.
Methods: SD rats (weighing 300~350g) were used to replicate the dynamic models of cellular proliferation and vascular remodeling after intimal denudation of rats carotid common arteries and the rats were randomly divided into sham-injured group (S group), injured group (I group) and injured+20 mg kg-1 CAPE-treated group (CAPE group). Animals were respectively killed after baloonlesions at different time points (3d, 7d, 14d or 28d). The injured sections were taken out and made into specimens for HE staining and elastic fiber staining. Neointimal thickness (H), neointimal area (NIA), media area (MA), internal elastic membrane (IEM) cross section area, external elastic membrane (EEM) cross section area and lumen area (LA) were measured by computer image analysis system, then the neointimal/media area ratio (NIA/MA) and lumen stenosis index (NIA/IEM) were calculated. The mean optical density values were employed to show the protein expression changes of Sur, Bax and Bcl-2 protein in the carotid wall cells by computer image analysis system. Terminal deoxynucleotidyl transferase (TdT) mediated dUTP-biotin nucle and labeling(TUNEL)determined the apoptosis in vessel wall. The changes of IL-6 and TNF-αin the serum were determined by ELISA. EMSA was used to examine nuclear factor of kappa B (NF-κB) activation in vessel wall. The expression levels of Sur, Bax and Bcl-2 mRNA in the tissues of carotid wall cells were detected with real-time quantitative PCR method.
Results: Pathomorphometrical analysis:Single layer endothelium was only showed in non-injury arteries(S group)at different time points. The proliferation of VSMCs was spotted on the surface of lumen at 3 d after balloon injury. The neointima had been formed and continuously thicken at 7 d after injury. The neointimal thickness and area as well as extracellular matrix were gradually increased after 14 d. The thickness and area of the media were gradually increased during 3 ~ 14 d,in which the medial area significantly increased at 14 d compared with non-injured vessel. Lumen area initially decreased at 3~ 7 d after injury. Lumen area after 14 d was significantly less than that of non-injured vessel. NIA/MA and NIA/IEM gradually slightly increased at 3 ~ 7 d after injury,it was maximal at 14 d. The indexes in CAPE group had contrary changes compared with I group.
Sur and Bcl-2 protein be detected mainly in VSMCs of arteries media. Their levels were very low, and they increased in I groups, CAPE can improve the states. Sur and Bcl-2 protein increased in I group and lowered after rats were administered CAPE. Bax protein were mainly detected in VSMCs of media of carotid wall and increases slightly in I group, after rats treated with CAPE, the level of Bax protein increased significantly in a time-dependent manner.
No cells TUNEL positive in S group. The cells positive increased in I group in early time but decreased later. CAPE increased the cells positive
The concentrations of IL-6 and TNF-αin S group in the serum increased slightly.Those in Igroup increased more remarkbly compared with S group. And CAPE inhibited the serection of L-6 and TNF-α.
NF -κB activation in balloon - injured arteries was examined by electrophoretic mobility shift assay. No detectable NF -κB activation was found in normal arteries, which was detected immediately following injury, peaked at 12 hours, lasted 48 h, returned to baseline at 72h.
Real-time quantitative PCR showed that the expression levels of Sur and Bcl-2 mRNA increased in I group compared with S group and they decreased in CAPE group compared with I group. And that of Bax showed a contrary change.
Conclusion: CAPE produced a significant inhibition of neointimal hyperplasia in rats carotid arteries after balloon dilation, the inhibition effect had an obviously time-dependent relationship and may partly be raleted to inhibit the expression of genes such as Sur and Bcl-2 which can spur the growthof cells and promote the expression of Bax gene which show an effect of inducing cell apotosis. Maybe it is one of the mechanisms of CAPE inhibiting neointimal hyperplasia after PCI.
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