体外培养间充质干细胞移植对颈动脉损伤后局部NO含量和eNOS mRNA表达的影响

目的经静脉移植MSCs治疗球囊损伤的粥样硬化颈动脉,探讨MSCs对动脉损伤后修复的影响及可能的作用机制。方法制作颈动脉粥样硬化狭窄动物模型48只,分为MSCs移植组(n=30)和对照组(n=18)。MSCs移植组于球囊损伤前经外周血采集MSCs并体外培养扩增,于球囊损伤后即刻、1周和2周经静脉移植MSCs,而对照组给予等量生理盐水。于球囊损伤后4周收集血管标本,经免疫化学染色后观察血管病理形态学特点、计算新生内膜和中膜面积、检测增殖细胞核抗原(PCNA)以及ELISA法测定局部NO含量和RT-PCR检测eNOSmRNA表达。结果血管病理形态学检测显示,MSCs移植组颈动脉内皮细胞少量缺失,但无内皮的片状剥脱,管壁部分区域轻度增厚,管腔轻度狭窄,增厚处中膜可见少量泡沫细胞沉积,部分区域伴少量纤维组织增生,呈动脉粥样硬化早中期(脂纹-纤维斑块期)改变。与对照组比较,MSCs移植组新生内膜面积(NEA)和中膜面积(MA)均明显减少(P0.05);而两组间新生内膜/中膜面积比(I/M)无统计学意义。同时,血管壁PCNA测定显示:MSCs移植组PCNA阳性细胞率显著低于对照组,表明与移植组相比,对照组新生内膜增生程度更为明显。MSCs移植组损伤的颈动脉局部NO含量和eNOSmR-NA表达均明显高于对照组,差异具有统计学意义。同时,eNOSmRNA表达程度与4周时动脉内膜增生情况相关分析显示呈负相关。结论 MSCs静脉移植可明显降低球囊损伤动脉的新生内膜增生,这可能与损伤动脉局部eNOSmRNA表达和NO含量增加有关。     

人参皂苷Rg3对大鼠颈动脉球囊损伤模型PCNA、CyclinD1及CDK4表达的影响

目的研究人参皂苷Rg3对大鼠颈动脉球囊损伤后增殖细胞核抗原(PCNA)、细胞周期蛋白(Cyclin) D1、细胞周期蛋白依赖性激酶(CDK) 4表达的影响。方法雄性SD大鼠30只,其随机分成假手术组,模型组,人参皂苷Rg3组(10 mg/kg)。用球囊建立大鼠颈动脉损伤模型,次日灌胃给药,连续14 d;利用苏木精-伊红(HE)染色观察损伤血管组织形态学的变化;利用Western印迹和Real-Time PCR法检测损伤血管组织中PCNA、Cyclin D1及CDK4的表达。结果与假手术组比较,模型组血管新生内膜明显增厚,内膜/中膜面积比明显增加,PCNA、Cyclin D1及CDK4的表达显著增强;与模型组比较,人参皂苷Rg3组损伤血管内膜增生明显减轻,内膜/中膜面积比明显下降,PCNA、Cyclin D1及CDK4的表达明显降低。结论人参皂苷Rg3可能是通过下凋PCNA的表达,抑制细胞周期相关蛋白Cyclin D1和CDK4的活性,从而减轻血管内膜增生。     

卡维地洛对大鼠颈动脉球囊损伤后血管内膜增生的影响

目的探讨卡维地洛(CAR)对大鼠颈动脉球囊损伤后内膜增生的影响。方法雄性Wistar大鼠36只,随机分为假手术组、损伤组和CAR组,每组12只,后2组建立大鼠颈动脉球囊损伤模型。3组均于术后7、14天分别处死6只大鼠。观察颈动脉形态学变化,计算新生内膜面积,免疫组织化学检测增殖细胞核抗原(PCNA)阳性细胞的表达。结果假手术组无新生内膜发生。与假手术组比较,损伤组大鼠术后7天,新生内膜形成并增厚,14天内膜增厚更明显(P0.01)。与损伤组比较,CAR组术后14天,新生内膜面积减少44%(P0.01),管腔面积增加82%(P0.01),内膜PCNA表达显著降低(P0.01)。结论 CAR可有效抑制颈动脉球囊损伤后内膜增生。     

骨髓间充质干细胞移植对兔颈动脉球囊损伤后再狭窄的影响

目的 探讨兔颈动脉行球囊损伤后,骨髓间充质干细胞(BMSC)移植对损伤血管内皮修复和再狭窄的影响.方法 建立兔颈动脉粥样硬化狭窄模型48只,随机分成BMSC移植组24只和对照组24只.体外培养BMSC,携带增强型绿色荧光蛋白(EGFP)的腺病毒转染标记后备用.颈总动脉球囊损伤后,以107个/kg的细胞数经颈外动脉移植到损伤动脉局部,对照组注射等量的PBS液.移植后1周取材行免疫组织化学检测BMSC归巢.移植后2周免疫组织化学染色检测血管内膜血小板-内皮细胞黏附分子(CD31)、α-平滑肌肌动蛋白(SM α-actin)及增殖细胞核抗原(PCNA)的表达;移植后4周行颈总动脉造影检测血管狭窄率,HE染色检测损伤血管新生内膜面积、新生内膜面积/中膜面积的变化.结果 BMSC移植组在术后1周损伤血管的内膜有表达EGFP的BMSC归巢.术后2周BMSC移植组血管内膜有连续性CD31的表达,对照组为阴性;BMSC移植组PCNA的表达较对照组明显降低(23.43％±2.80％比50.49％±3.60％,P＜0.05),而BMSC移植组SM α-actin的表达较对照组明显增加(0.437±0.049比0.197 ±0.032,P＜0.01).术后4周HE结果显示:BMSC移植组血管新生内膜面积(0.103±0.022比0.214±0.024,P＜0.01)、新生内膜/中膜面积(0.771±0.096比1.646±0.223,P＜0.01)均较对照组减轻;颈动脉造影结果显示:BMSC移植组较对照组血管再狭窄率减轻(39.64％±2.30％比63.31％±2.82％,P＜0.05).结论 移植BMSC可促进颈动脉球囊损伤后早期再内皮化和血管平滑肌细胞表型转化,抑制血管新生内膜的增生,减轻了血管再狭窄.     

全反式维甲酸对兔颈动脉粥样硬化病变中Cdk2表达及血管平滑肌细胞增生的影响

目的探讨全反式维甲酸(ATRA)对兔颈动脉粥样硬化病灶中血管内膜的增生、血管平滑肌细胞(VSMCs)增殖、增殖细胞核抗原(PCNA)及细胞周期素依赖性激酶Cdk2表达规律的影响。方法36只新西兰雄性大白兔随机分为3组:正常饮食组、手术组、ARTA治疗组,每组12只。手术组和治疗组均给予高脂饮食,两周后用空气干燥法制作颈动脉内膜损伤模型,治疗组于术前3d开始给予ATRA灌胃。于术后1、4周处死动物,取病变血管应用HE染色、免疫组化和计算机图像分析法进行形态学、PCNA和Cdk2表达水平的检测。结果①正常动脉壁未见PCNA及Cdk2表达。②手术组在术后第1周时内膜开始增生,第4周增生明显,且出现泡沫细胞、脂质核心形成、管腔狭窄;增生内膜中Cdk2表达水平增高。③治疗组Cdk2的表达明显低于手术组(P<0.05),VSMCs的迁移、增殖、内膜增生和管腔狭窄显著减轻(P<0.05)。④PCNA表达与Cdk2表达呈显著正相关(P<0.01)。结论ARTA可通过抑制Cdk2表达,抑制VSMCs的迁移和增殖,从而抑制兔颈动脉粥样硬化新生内膜过度增生和管腔狭窄。     

骨髓间充质干细胞移植对大鼠血管成形术后内膜增生及炎症因子表达的影响

目的探讨大鼠血管成形术后,骨髓间充质干细胞(BMSCs)移植对血管新生内膜增生及炎症因子表达的影响。方法制作大鼠颈动脉球囊损伤模型48只,随即分成对照组和BMSCs组,每组24只。标记的BMSCs移植到大鼠,对照组注射等量的PBS液。术后取血管组织行免疫组织化学染色检测核转录因子-κBp65(NF-κBp65)、α-平滑肌肌动蛋白(α-SMA)及增殖细胞核抗原(PCNA)的表达;HE染色血管组织检测血管形态学变化。术后ELISA检测血清炎症因子的浓度。结果术后14 d,BMSCs组损伤血管局部NF-κBp65、PCNA及α-SMA的表达均较对照组明显减少(P<0.05)。术后28 d,BMSCs组新生内膜面积、新生内膜/中膜面积均较对照组显著减少(P<0.05)。与对照组比较,术后BMSCs组血清TNF-α的浓度明显降低(P<0.01),而IL-10水平显著升高(P<0.01)。结论 BMSCs可发挥免疫调节作用,改善血管炎症反应,抑制血管新生内膜增生。     

犬冠状动脉支架植入术后细胞凋亡及凋亡相关基因蛋白表达的变化

目的观察犬冠状动脉支架植入术后血管内膜凋亡及凋亡相关基因蛋白表达的动态变化.方法15只犬进行冠状动脉左回旋支支架植入术,前降支相应血管作为对照,分别于术后1周、4周和12周处死,进行病理学检查、TUNEL法和透射电镜检测凋亡细胞、PCNA和Bcl-xl免疫组织化学染色以及Bcl-xl蛋白质印迹杂交.结果支架植入术后1～12周内膜面积持续增加;正常血管未见凋亡细胞和PCNA阳性细胞,术后1周内膜中凋亡细胞阳性率和PCNA阳性细胞率均达高峰,术后4周和12周不断降低,但凋亡细胞阳性率在各时间段均低于PCNA阳性细胞率;Bcl-xl免疫组织化学染色和蛋白印迹杂交均显示正常对照血管偶见表达,术后1周在内膜中表达增加,术后4周在内膜中大量表达,并可维持至12周.结论细胞凋亡相对不足可能是支架植入术后再狭窄形成的一个原因,Bcl-xl在内膜中高表达可能是造成细胞凋亡相对不足的因素之一.     

依维莫司对大鼠颈总动脉球囊损伤后内膜增生的影响

目的:探讨依维莫司对大鼠颈总动脉球囊损伤模型增生内膜的影响及其可能作用机制.方法:健康雄性SD大鼠36只,随机分为假损伤组(对照组)、颈总动脉球囊损伤组(损伤组)和颈总动脉球囊损伤+口服依维莫司组(依维莫司组),每组12只.依维莫司组于颈总动脉球囊损伤前1天,用依维莫司负荷剂量1.5 mg/kg灌胃,随后给予其剂量0.75 mg·kg-1·d-1灌胃直至第28天,对照组与损伤组给予等量0.9%氯化钠溶液灌胃.各组均于术后第28天取颈总动脉损伤段,观测颈动脉形态学变化,以免疫组化法测定损伤血管内膜真核翻译起始因子4E(eIF-4E)及增殖细胞核抗原(PCNA)的表达情况.结果:对照组血管内膜无增生,eIF-4E、PCNA表达极少;与对照组比较,损伤组新生内膜形成并增生明显,eIF-4E、PCNA表达显著增强;依维莫司组较损伤组新生内膜增生减轻,eIF-4E及PCNA表达明显降低,差异有统计学意义(P＜0.05).结论:依维莫司可抑制大鼠颈总动脉球囊损伤模型新生内膜增殖.其作用机制可能与抑制eIF-4E及PCNA表达有关.     

罗格列酮对大鼠胸主动脉球囊损伤后内皮再生和内膜增生的影响

目的探讨罗格列酮(rosiglitazone,RSG)对血管损伤后内皮再生和内膜增生的影响。方法制备大鼠胸主动脉球囊损伤模型,将SD大鼠随机分为RSG组、对照组和假手术组,于术后第7天和第14天处死动物。分别进行伊文思蓝染色观察内皮覆盖情况,细胞核增殖抗原(PCNA)免疫组化染色和组织形态学定量分析,并测量损伤后14 d时各组血清一氧化氮(NO)含量。结果RSG 7 d组和14 d组的再生内皮覆盖率分别为38.2%和75.2%,均较对照组(32.4%和60.4%)显著增加(P<0.05和P<0.01),且RSG 14 d组血清中的NO含量较对照组升高。球囊损伤后7 d内膜开始有少量增生,14 d时形成明显的新生内膜。RSG使损伤后14 d形成的新生内膜显著减少,内膜面积与中膜面积的比值(IA/MA)较对照组降低60.9%。与对照组比较,RSG 7 d组和14 d组新生内膜内的PCNA阳性表达指数均显著减少。结论RSG可以促进大鼠胸主动脉球囊损伤处的内皮再生,并减少新生内膜的形成。     

Kindlin-2 RNA干扰减轻大鼠颈动脉内膜增生

目的观察Kindlin-2 RNA干扰对球囊损伤的大鼠颈动脉内膜增生的影响。方法构建并制备Kindlin-2 siRNA和阴性对照慢病毒载体并感染球囊损伤的大鼠颈动脉,1周和4周后取损伤的颈动脉,实时定量PCR检测Kindlin-2 mRNA的表达,HE染色评估术后4周颈动脉内膜增生情况,并行免疫荧光或免疫组化检测颈动脉中Kindlin-2、α-actin、PCNA和β1整合素的表达,Masson染色了解颈动脉中胶原纤维合成情况。结果 Kindlin-2RNA干扰能明显降低1周时颈动脉中Kindlin-2 mRNA的表达水平(P0.05),并显著抑制4周后颈动脉的内膜增生(P0.05)。与阴性对照组相比,Kindlin-2 siRNA组术后4周颈动脉中Kindlin-2、α-actin、PCNA和β1整合素的表达水平均明显降低,颈动脉内膜和中膜胶原纤维的合成也减少。结论 Kindlin-2 RNA干扰可能通过抑制血管平滑肌细胞增殖、迁移和细胞外基质合成减轻血管内膜增生。     

Effect of Probucol on Smooth Muscle Cell Proliferation and Dedifferentiation After Vascular Injury in Rabbits: Possible Role of PDGF

We previously reported a clinical study in which probucol reduced the restenosis rate. The mechanism of this effect is unclear. Restenosis is characterized by neointimal hyperplasia caused by proliferation of smooth muscle cells (SMCs), which increases the expression of Platelet-derived growth factor (PDGF)-A and SMemb. SMemb, a non–muscle-type myosin heavy chain most predominantly expressed in embryonic smooth muscle, can be used as a good molecular marker for dedifferentiated SMC. The aim of this study was to analyze the effect of probucol on neointimal proliferation and the level of expression of PDGF-A and SMemb after balloon injury in rabbits. Probucol was given orally 1.3 g/d from 2 weeks prior to carotid balloon injury to the time of killing (2 or 4 weeks after balloon injury). Intimal area was determined histologically using a computerized morphometry program. For quantification of SMC proliferation, alpha-actin–positive cells and proliferating cell nuclear antigen (PCNA)-labeled cells were counted. The expression of PDGF-A and SMemb mRNA was analyzed by the RNase protection assay. SMemb expression was also examined by immunohistochemistry. Probucol remarkably decreased intimal area by 70% and the number of SMC and PCNA-labeled cells in the intima. The expression of PDGF-A mRNA was significantly increased after balloon injury in untreated rabbits, whereas it was markedly suppressed with probucol treatment. The expression of SMemb was significantly increased in injured arteries at mRNA and protein levels. However, probucol did not suppress SMemb expression. Probucol is effective in preventing SMC proliferation, which is possibly due to a decrease in the expression of PDGF.     

Probucol inhibits in-stent thrombosis and neointimal hyperplasia by promoting re-endothelialization

BACKGROUND: Evidence suggests that delayed re-endothelialization is responsible for in-stent thrombosis. Probucol inhibits neointimal thickening in animals via enhanced re-endothelialization and is the only oral drug that consistently inhibits restenosis after coronary angioplasty in humans. Here, we examined the effects of probucol on re-endothelialization and neointimal formation in a stent model. METHODS AND RESULTS: New Zealand White rabbits were fed a hypercholesterolemic diet with probucol (1%) or without (control) (n=11 each) for 6 weeks. At 2 weeks, endothelial denudation and stenting of the iliac artery was performed. Iliac arteries were harvested at week 6, and stented segments sectioned and analyzed. Compared with control, probucol increased in-stent re-endothelialization (74+/-6% in controls versus 93+/-3% in probucol-treated; P=0.008), and decreased average luminal stenosis (58+/-27 versus 31+/-16%; P=0.01) and stent depth (619+/-310 versus 314+/-158 microm; P=0.009). Compared with control, probucol also decreased accumulation of macrophages in the neointima. Furthermore, none of the probucol-treated rabbits had in-stent thrombosis, whereas four of eleven control rabbits showed thrombosis (P=0.04). CONCLUSIONS: Probucol demonstrates anti-restenotic and appears to have anti-thrombotic properties that are likely related to its ability to promote in-stent re-endothelialization.     

Effect of probucol on repeat revascularization rate after percutaneous transluminal coronary angioplasty (from the Probucol Angioplasty Restenosis Trial [PART])

To address the issue of whether probucol reduces clinical events after percutaneous transluminal coronary angioplasty (PTCA), we surveyed clinical status at 1 year after PTCA of 101 patients who had entered the Probucol Restenosis Angioplasty Trial. Repeat angioplasty at index lesions were required in 5 patients in the probucol group and in 12 in the control group, suggesting that probucol administered beginning 4 weeks before PTCA reduces repeat revascularization rates for 1 year.     

Effects of probucol versus aspirin and versus brachytherapy on restenosis after femoropopliteal angioplasty: the PAB randomized multicenter trial.

PURPOSE: To evaluate the effect of probucol and/or of endovascular brachytherapy (EVBT) on restenosis after percutaneous transluminal angioplasty (PTA) of femoropopliteal arteries. METHODS: A total of 335 patients (206 men; mean age 72+/-9 years) with intermittent claudication were randomized according to a 2x2 factorial design to 1 of the 4 groups: probucol, placebo, EVBT, and EVBT+probucol. Probucol (1 g/d) or placebo were given in double-blinded fashion 1 month before and for 6 months after PTA. Gamma irradiation (192Iridium, 14 Gy, 5-mm reference depth) was randomly applied in an unblinded manner from a noncentered endoluminal catheter. All patients received aspirin (100 mg/d). Primary endpoint was restenosis (>50% diameter reduction) detected by duplex ultrasound 6 months after PTA. Secondary endpoints included clinical and hemodynamic assessment. RESULTS: Restenosis in patients undergoing EVBT was 17% (23/133) versus 35% (50/142) in patients without EVBT (p<0.001); in patients treated with probucol versus placebo, the rates were 23% (31/135) and 30% (43/140, p<0.001). Three quarters (77%, 102/133) of patients were free of claudication after EVBT therapy versus 61% (87/142) without EVBT (p<0.05). Need for target vessel revascularization was 6% (8/133) with EVBT versus 14% (20/142) without EVBT (p<0.01). Late thrombotic occlusions occurred in 4% (6/133), exclusively in patients treated with EVBT after stent implantation. CONCLUSIONS: Endovascular brachytherapy significantly reduces restenosis, improves symptoms, and reduces reinterventions after PTA of femoropopliteal arteries. Probucol reduces restenosis but has no additive effect when combined with brachytherapy.     

转导C型钠尿肽基因对血管成形术后血管平滑肌细胞增殖的影响

目的观察局部转导C型钠尿肽基因对损伤后血管平滑肌细胞增殖的影响。方法将84只雄性新西兰大白兔随机均分为正常、对照和实验3组。后2组高脂饮食喂养,并以球囊损伤兔髂动脉建立再狭窄模型。对照组局部转导逆转录病毒载体携带的碱性磷酸酶基因;实验组局部转导逆转录病毒载体携带的C型钠尿肽基因。于术后第3天、第1周末、第2周末和第4周末取损伤段动脉进行氚标胸腺嘧啶脱氧核苷掺入实验和增殖细胞核抗原免疫组织化学检测,采用计算机图像分析仪测量血管腔面积、内膜厚度、内膜面积、内膜与中膜面积比。结果对照组和实验组在后3天血管内膜面积、内膜厚度、内膜/中膜比值开始逐渐增加,术后2周上述各值显著增加,但实验组上述指标明显低于对照组(后第3天、第1周时P<0.05,后第2周、第4周时P<0.01)。氚标胸腺嘧啶脱氧核苷掺入实验发现,术后第3天,对照组和实验组氚标胸腺嘧啶脱氧核苷掺入量开始增加,但两组无显著差异(P>0.05);术后第1周,实验组氚标胸腺嘧啶脱氧核苷掺入量明显低于对照组(P<0.05),术后4周时,实验组氚标胸腺嘧啶脱氧核苷掺入量已降至接近正常水平(P>0.05),而对照组氚标胸腺嘧啶脱氧核苷掺入量增加值仍高于正常组(P<0.01)。增殖细胞核抗原免疫组织化学显示对照组髂动脉损伤后2周在内膜层可见大量增殖细胞核抗原阳性细胞,而实验组增殖细胞核抗原阳性细胞表达不显著。结论局部转染C型钠尿肽基因可有效抑制血管成形术后血管平滑肌细胞增殖及内膜增生。     

Effect of BO-653 and probucol on c-MYC and PDGF-A messenger RNA of the iliac artery after balloon denudation in cholesterol-fed rabbits

Antioxidants have been proposed as a promising treatment for restenosis after percutaneous transluminal coronary angioplasty (PTCA), but their mechanism of action remains unclear. Here, we investigated the effect of antioxidants on gene expression in the artery after balloon denudation. We developed a sensitive ribonuclease (RNase) protection assay for the messenger RNA (mRNA) levels of immediate early (IE) genes (c-jun, c-fos and c-myc), as well as platelet-derived growth factor-A (PDGF-A), platelet-derived growth factor-beta receptor, transforming growth factor-beta 1, and vascular endothelial growth factor. New Zealand White rabbits were fed a 0.17% cholesterol diet containing vehicle, BO-653 or probucol, and balloon denudation for iliac arteries was performed. The iliac arteries were then removed at 4 h after the denudation, for IE genes, and 10 days after for growth factors and receptors. Both BO-653 and probucol significantly reduced neointimal thickening, compared with the control. In terms of gene expression, BO-653, but not probucol, significantly inhibited c-myc induction. On the other hand, probucol, but not BO-653, significantly inhibited PDGF-A expression. Neither treatment had any effect on the expression of other genes. These results suggest that antioxidants affect the gene expression of the neointimal response and that both BO-653 and probucol inhibit gene expression in specific manners.     

Differential expression of cell proliferation regulatory proteins in B- and T-lineage acute lymphoblastic leukaemias

In order to better understand the molecular background of differences between the clinical picture of T- and B-lineage ALLs, we studied the expression of several proteins involved in the regulation of cell proliferation in bone marrow blast cells from 30 cases of previously untreated acute lymphoblastic leukaemia (ALL); 14 cases were T- and 16 B-cell lineage ALLs. We studied several cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk6) and cyclins (cyclin A, cyclin B1, cyclin D3 and cyclin E). We also studied proliferating cell nuclear antigen (PCNA) and Bcl-2 expression, the latter protein known to be involved in the prolonged survival of B-lineage ALL blasts. Proteins obtained from cell lysates were resolved on polyacrylamide gel followed by immunodetection and densitometry of specific bands. Expression of cdk1 and PCNA, markers of proliferative activity, was significantly higher in T- than in B-lineage ALL. Cdk6, which was highly correlated to PCNA, was also higher in T-cell ALL. In contrast, B-lineage ALL displayed a higher expression of anti-apoptotic protein Bcl-2. We hypothesize that those particularities may reflect differential roles of cell multiplication and apoptosis in the neoplastic proliferation of B- and T-lineage ALL.     

Ethanol reduces p38 kinase activation and cyclin D1 protein expression after partial hepatectomy in rats

BACKGROUND/AIMS: Chronic ethanol consumption inhibits liver regeneration. We examined the effects of chronic ethanol consumption on two mitogen-activated protein kinases in relation to induction of cell cycle proteins after partial hepatectomy (PH). METHODS: Male Wistar rats were ethanol-fed (EF) or pair-fed (PF) for 16 weeks before PH. Hepatic activation of extracellular signal regulated kinase (ERK)1/2, p38 kinase and expression of cyclinD1, cyclin-dependent kinase-4 (cdk4) and proliferating cell nuclear antigen (PCNA) were studied. RESULTS: In PF rats, PH-induced p38 activation was evident at 2h and was maximal at 12h. There was a close temporal relationship between p38 activation, cyclin D1 and PCNA expression. Alcohol exposure reduced p38 activation, cyclin D1 and PCNA, each by approximately 50%. ERK1/2 activation occurred during the first 2h post-PH in both EF and PF rats, and there was no later increase in PF rats. In vivo inhibition of p38 suppressed PCNA expression whereas the effect of ERK1/2 inhibition was inconsistent. CONCLUSIONS: p38 kinase activation is linked temporally with cyclin D1 expression after PH and appears to exert cell cycle control in the adult liver. p38 signaling also appears to be a target for the inhibitory effect of chronic alcohol on liver regeneration.     

Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit.

Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.     

缬沙坦对兔动脉成形术后血管内膜增生及ICAM-1表达的影响

目的观察缬沙坦对兔动脉成形术后血管内膜增生及细胞间黏附分子-1（ICAM-1）表达的影响。方法雄性新西兰白兔24只，随机分成三组，对照组给予普通饲料12周；模型组和缬沙坦组予高胆固醇喂养8周后行球囊成形术；缬沙坦组给予缬沙坦干预治疗4周。三组均取腹主动脉行病理形态学观察及ICAM-1免疫组织化学分析。结果缬沙坦组较模型组内膜厚度及面积明显减小（P〈0．01）。免疫组织化学分析显示，缬沙坦组与模型组相比ICAM-1表达显著减少（P〈0．01）。结论缬沙坦可以显著减轻兔腹主动脉成形术后内膜增生，其机制可能与抑制血管内膜ICAM-1表达，从而抑制损伤内膜炎症反应有关。