血管平滑肌细胞的表型标志α-SM-actin的表达与调控的研究进展

存在于血管壁中膜的血管平滑肌细胞 (VSMC)根据其结构和功能的不同可分为收缩型和合成型两种表型(phenotype)。VSMC向合成型转化是 VSMC增生从而引起动脉粥样硬化和血管再狭窄等心血管疾病的先决条件。拟就国内外学者关于 VSMC两种表型转化时其表型标志 α-SM-actin的表达与调控的研究进展作一综述     

多西环素及吲哚美辛对大鼠主动脉损伤后狭窄的早期预防作用的研究

<正>动脉损伤存在于一系列疾病病变中,例如动脉粥样硬化、冠状动脉移植的血管狭窄、动脉栓塞取栓术后再狭窄等。心血管系统在损伤后,包括经皮腔内血管成形术后6个月内血管再狭窄率为25%⁵0%[1],严重影响了手术的治疗效果。目前的研究表明:多个机制参与动脉损伤后的狭窄过程,并且认为细胞外基质(ECM)的重建,尤其胶原纤维的重建(collagenⅠ和collagenⅢ)和血管平滑肌细胞(VSMC)迁移、增生有密切的关系[2]。基质金属蛋白酶(MMP)是参与ECM降解的最主要的酶,且能促进VSMC迁移增殖,导致新生内膜增生和血管重塑,最终导致血管狭窄。鉴于MMP在血管损伤后狭窄中的重要作用,抑制MMP的表达及活性成为预防血管     

可溶性支架转染c-myc基因反义寡核苷酸对静脉桥c-myc基因mRNA表达的影响

目的选择c-myc为靶基因,在兔颈总动脉颈外静脉移植模型中采用可溶性支架将反义c-myc寡核苷酸转染静脉桥,旨在从核酸mRNA水平明确c-myc基因在静脉桥再狭窄机制中的作用。方法新西兰大耳白兔随机分成5组,每组10只动物。①空白对照组;②单纯可溶性支架组;③正义寡核苷酸可溶性支架组;④反义寡核苷酸可溶性支架组;⑤不匹配寡核苷酸可溶性支架组。建立兔颈外静脉颈总动脉旁路移植术模型,合成c-myc寡核苷酸,处理可溶性支架,依组别不同,在静脉移植时静脉桥管腔内分别置入:①空白对照;②单纯可溶性支架;③反义寡核苷酸可溶性支架;④正义寡核苷酸可溶性支架;⑤不匹配寡核苷酸可溶性支架;于颈外静脉移植后7天、28天和90天取出静脉桥。采用原位杂交及NorthernBlot,半定量及定量地检测各组静脉桥中c-myc基因mRNA表达水平。结果原位杂交:同时间段反义寡核苷酸组细胞胞浆与胞核内c-myc基因mRNA的表达明显降低,其他各组静脉桥c-myc基因mRNA强烈表达,斑点杂交及Northern杂交印迹扫描数值显示7天、28天、90天空白对照组、空白支架组、正义组、错配组RNA的表达显著强于同时间点的反义寡核苷酸组RNA表达水平,而同时间点除外反义寡核苷酸可溶性支架组的其他各组之间无差异。结论可溶性支架转染c-myc基因反义寡核苷酸可显著抑制移植物内c-myc基因的表达。     

他汀类药物与血管平滑肌细胞凋亡

血管平滑肌细胞（VSMC）的异常增殖和迁移在粥样斑块形成和冠状动脉介入治疗（PCI）后再狭窄中起非常重要的作用。他汀类药物不仅是一种有效的调脂药，同时还有多种调脂以外的作用。如他汀类药物可以抑制VSMC的增殖和迁移，并诱导其凋亡。临近病变部位的中层VSMC的凋亡可能造成斑块纤维帽容易破裂，进而引起斑块不稳定和临床事件。但研究证实他汀类药物有稳定斑块的作用，且新生内膜VSMC对他汀类药物诱导的凋亡作用比普通的血管中层VSMC更敏感。因此，他汀类药物的促新生内膜VSMC凋亡作用可能对预防PCI术后再狭窄起有益作用。具体作用机制以及临床上如何合理发挥此类作用尚待进一步研究。     

缬沙坦对球囊损伤后血管平滑肌细胞增生的影响

目的 探讨缬沙坦因子防治人类血管成形术后再狭窄的可行性方法观察新的非肽类血管紧张素Ⅱ的Ⅰ型(AT_1)受体拮抗剂,缬沙坦(Valsartan),对血管平滑肌细胞(VSMC)增生的影响。对大鼠髂动脉球囊内皮剥脱术后过度增生模型采用~3H-TdR和~3H-Leu掺入,免疫组化染色检测VSMC中增殖细胞核抗原(PCNA)的表达及图象分析血管壁形态学变化。结果 缬沙坦显著减少~3H-TdR和~3H-Leu的掺入量,减少新生内膜面积和PCNA阳性细胞数。结论 缬沙坦能抑制大鼠动脉的球褒内皮损伤后的VSMC增生,可能它是防治血管成形术再狭窄的有效药物。     

药物涂层支架--介入心脏病学跨世纪的进展

经皮冠状动脉腔内成形术 (PTCA)和支架置入术后最突出的问题是术后 3～ 8个月再狭窄 ,单纯球囊扩张术后再狭窄发生率高达 30 %～ 5 0 %。其机制主要由于血管局部对球囊损伤的过度愈合反应所致 ,包括早期血管弹性回缩、晚期血管负性重塑(remodeling)及新生内膜过度增生。支架置入术由于有效地制止了血管弹性回缩和负性重塑 ,使再狭窄率明显降低。但由于动脉壁损伤、血栓形成及炎性反应 ,刺激各种生长因子和细胞因子产生 ,通过血管平滑肌 (VSMC)受体 ,使平滑肌细胞分裂 ,导致平滑肌细胞增生 ,基质分泌 ,平滑肌细胞向内膜迁移 ,使新生内膜…     

PTEN及其在血管成形术后再狭窄中作用的研究进展

随着血管成形术在冠状动脉粥样硬化性心脏病(CAD)治疗上的广泛应用,血管成形术后再狭窄成为影响术后效果的主要因素。血管平滑肌细胞(vascular smooth muscle cell,VSMC)是血管壁的主要成分,VSMC的增殖及迁移在血管成形术后的再狭窄过程中起重要作用。肿瘤抑制因子PTEN是最近发     

诱导型NOS在动脉内膜损伤后的自然表达过程

一氧化氮(NO)是重要的细胞内及细胞间的信号分子,它由 L-精氨酸(L-Arg )经一氧化氮合酶(NOE)催化产生。NO在维持血管张力,调节血管平滑肌细胞(VSMC)增生和控制血小板及白细胞对内皮粘附起重要作用。近年来研究表明诱导型NOS(iNOS)在动脉损伤后的新内膜和VSMC3恐醒8速被诱导产生同时伴NO生成,NO在预防动脉粥样硬化及再狭窄形成起一定作用[1-2]。本研究目的是了解iNOS在大鼠颈动脉损伤处的表达特点,以揭示iNOS表达的自然过程及作用。 材料与方法 1.模型制作选 300～330 g雄性wistar大鼠20只,以成巴比妥 50 mg/kg行腹膜外麻醉,沿…     

多沙唑嗪对PTCA术后再狭窄的防治作用机制

经皮冠状动脉腔内成形术(PTCA)已广泛成功地应用于冠状动脉粥样硬化性心脏病患者的治疗，随着手术经验积累和设备改进，其即刻成功率已高达90％以上，然而再狭窄仍是PTCA术后存在的主要临床问题。多中心大规模研究结果显示，PTCA术后的患者中再狭窄率仍达22％—32％。再狭窄的原因部分为机械因素所致，如血管夹层和弹性回缩、而生物因素如冠状动脉内血栓形成和平滑肌细胞(VSMC)过度增生、迁移至内膜则更为重要。能够作用于细胞周期、抑制平滑肌增殖的药物有可能对治疗再狭窄有效。已有报道表明，抗高血压药多沙唑嗪就具有这种作用。现就其一般性状及作用机制做一简要综述。     

丝裂素活化的蛋白激酶反义寡脱氧核苷酸防治血管内膜增殖

目的：探讨Ca^2 -钙调蛋白依赖性蛋白激酶（丝裂素活化的蛋白激酶）（CCDPK）在生长因子诱导体外培养大鼠血管平滑肌细胞增殖中的作用及反义CCDPK寡脱氧核苷酸（ODN）对球囊损伤后大白鼠血管内膜增生的抑制作用。方法：利用脂质体转染17－mer CCDPK反义ODN进入培养的血管平滑肌细胞以抑制CCDPK活性,设正义及随机ODN作对照。用蛋白质印迹法测定CCDPK表达。[^3H]胸腺嘧啶核苷酸掺入测定平滑肌细胞DNA合成。用2F球囊导管造成大白鼠颈动脉再狭窄模型,利用多聚胶F127－ODN系统由血管外膜部位给药。于损伤后2周取样,固定及HE染色观察内膜增生情况。FITC标记的ODN观察体内外给药方法的分布及吸收情况。结果：CCDPK反义ODN能明显抑制PDGF及ET诱导的CCDPK蛋白表达及[^3H]胸腺嘧啶核苷酸掺入。在大鼠颈动脉再狭窄模型,能明显抑制血管内膜增生。结论：CCDPK介导了PDGF及ET诱导的血管平滑肌细胞增殖。针对p42-和p44-CCDPK起始部位设计的17－mer反义ODN能有效抑制生长因子诱导的血管平滑肌细胞的增殖及球囊损伤大鼠血管内膜增生。     

Pharmacological treatment for prevention of restenosis

Coronary artery disease (CAD) is the leading cause of mortality and morbidity among adults in the Western world. Coronary artery bypass grafting and percutaneous coronary interventions (PCI) have gained widespread acceptance for the treatment of symptomatic CAD. There has been an explosive growth worldwide in the utilisation of PCI, such as balloon angioplasty and stenting, which now accounts for over 50% of coronary revascularisation. Despite the popularity of PCI, the problem of recurrent narrowing of the dilated artery (restenosis) continues to vex investigators. In recent years, significant advances have occurred in the understanding of restenosis. Two processes seem to contribute to restenosis: remodelling (vessel size changes) and intimal hyperplasia (vascular smooth muscle cell [VSMC] proliferation and extracellular matrix [ECM] deposition). Despite considerable efforts, pharmacological approaches to decrease restenosis have been largely unsuccessful and the only currently applied modality to reduce the restenosis rate is stenting. However, stenting only prevents remodelling and does not inhibit intimal hyperplasia. Several potential targets for inhibiting restenosis are currently under investigation including platelet activation, the coagulation cascade, VSMC proliferation and migration, and ECM synthesis. In addition, new approaches for local drug therapy, such as drug eluting stents, are currently being evaluated in preclinical and clinical studies. In this article, we critically review the current status of drugs that are being evaluated for restenosis at various stages of development (in vitro, preclinical animal models and human trials).     

Gene therapy of fibroproliferative vasculopathies: current ideas in molecular mechanisms and biomedical technology

Intimal hyperplasia occurs primarily as a part of the pathogenesis of coronary artery disease or secondary to therapeutic intervention in relieving vascular occlusion. Intimal hyperplasia involving vascular smooth muscle cells is found in atherosclerosis, post-balloon angioplasty restenosis, in-stent restenosis and vein graft disease, predominantly involving the use of saphenous vein conduits in coronary artery bypass grafting procedures. One potentially exciting area is that of gene therapy. Gene and protein expression patterns at the site of vasculoproliferative lesions have been widely studied and several target areas have been identified on the basis of whether the gene has an antiproliferative, proapoptotic, matrix degrading or endothelial protective action. Blood vessels are easily accessible for the delivery of the gene product, and experimental studies using animal models have used catheter-delivered gene products at the site of vascular injury. Currently, the application of antisense technology and adenoviral vector-mediated delivery has shown significant promise, albeit in in vitro or animal model settings. In this review, we discuss the current knowledge in the application of gene therapy in fibroproliferative vasculopathies. We examine some of the cellular mechanisms and intermediaries which could be potential candidates for gene targeting. We also present some of the advances in biomedical technology that might provide useful vehicles for pinpoint delivery of the gene product. Could the future of restenosis treatment be in gene therapy or is it misplaced enthusiasm?     

非体外循环冠状动脉旁路移植术后影响桥血管中远期通畅率的危险因素

【摘要】 目的 分析非体外循环冠状动脉旁路移植术(OPCABG)后桥血管的中远期通畅率及其危险因素。方法 OPCABG术后复查的患者113例。根据搭桥术后再血管化的程度分为通畅组和病变组,比较2组的性别、年龄、既往病史和血脂情况。采用多因素Logistic回归分析OPCABG术后影响桥血管中远期通畅率的危险因素。结果 2组间性别、OPCABG术后随访时间、旁路血管数量、术后再发心绞痛比较,差异有统计学意义。女性和旁路血管数量增加是影响OPCABG术后桥血管通畅的危险因素。结论 OPCABG术后的中远期通畅率与性别、旁路血管数量密切相关。     

Effect of nimodipine on subintimal hyperplasia of autologous vein bypass grafts in rats: a placebo-controlled study.

Autologous vein grafts are commonly used conduits for coronary bypass grafts. However, as many as 20% of the grafts may occlude in the first year to a subintimal hyperplasia. Although the initiating mechanism remains unclear, it has been demonstrated that subintimal hyperplasia is dependent upon smooth muscle cell proliferation and migration from the medial to the intimal layer. The present study focused on the prevention of smooth muscle cell proliferation using a calcium antagonist. A vein bypass graft from the jugular vein on the abdominal aorta was performed in 40 rats, divided into two groups of 20. Animals in the treated group received nimodipine (15 mg/kg of body weight), and those of the control group received a placebo. Nine months after grafting, the results showed that the group receiving nimodipine presented no or only slight subintimal hyperplasia as compared with the placebo group (p less than 0.001). The data presented in this study show that nimodipine can reduce subintimal hyperplasia in rats and strongly suggest that a calcium antagonist could be employed in the prevention of venous graft disease.     

Soluble N-cadherin: A novel inhibitor of VSMC proliferation and intimal thickening

Reoccurrence of symptoms occurs in 30–50% of coronary artery disease patients receiving vein grafts or bare-metal stents due to intimal thickening (restenosis). Restenosis is caused by vascular smooth muscle cell (VSMC) migration and proliferation. New therapeutic approaches that reduce VSMC migration and proliferation while promoting endothelial cell (EC) coverage are required. We assessed the effect of a soluble form of N-cadherin (SNC-Fc, a fusion of the extracellular portion of N-Cadherin to a mutated Fc fragment of IgG), a cell–cell junction molecule, on human saphenous VSMC proliferation and migration in vitro. We also assessed its effect on intimal thickening in a validated human ex vivo organ culture model. We observed that SNC-Fc significantly inhibited VSMC proliferation and to a lesser extent migration. The anti-proliferative effect of SNC-Fc was mediated by the interaction of SNC-Fc with the FGFR, rather than through inhibition of β-catenin signalling. SNC-Fc also significantly reduced intimal thickening by ~ 85% in the ex vivo organ culture model. SNC-Fc treatment inhibited proliferation of the intimal cells but did not affect migration. SNC-Fc reduced EC apoptosis, without detrimental effects on EC proliferation and migration in vitro. Importantly SNC-Fc increased EC coverage in the ex vivo model of intimal thickening. In conclusion, we suggest that SNC-Fc may have potential as an anti-proliferative therapeutic agent for reducing restenosis which has no detrimental effects on endothelial cells.     

桥血管的内膜损伤与狭窄

冠状动脉旁路移植术(CABG)后,桥血管狭窄是一个受到多因素影响、级联式变化的生理病理过程,发生、发展的机制复杂。通过查阅国内外相关文献,现就高血压、血脂异常、高血糖、缺血、缺氧、感染、炎性等因素可能引起的桥血管内膜损伤导致桥血管狭窄的研究现状作一综述。     

Surgical trauma and vein graft failure: further evidence for a role of ET-1 in graft occlusion

The saphenous vein (SV) is the most commonly used conduit for coronary artery bypass surgery. However, using traditional techniques, the occlusion rate for the SV is high, with over 50% of grafts failing within 10 years. In conventional coronary artery bypass surgery the SV is exposed to considerable damage during preparation for grafting. Recently, an increased graft patency has been described using a 'no-touch' technique, whereby the vein is prepared with minimal vascular trauma. There is evidence that the success of this form of coronary artery bypass surgery is a result, at least in part, of the retention of tissue-derived nitric oxide. We have examined the effects of conventional SV harvesting on vessel morphology, cell proliferation, endothelin-1 and its receptors. Considerable damage was observed in veins prepared using conventional surgery compared to 'no-touch' veins. The vessel wall exhibited evidence of surgical trauma, with regions of denudation of the luminal endothelium caused by distension. Endothelin-1 and endothelin-A receptors were present at subintimal regions of conventional SV segments where proliferating cells were identified. Endothelial endothelin-B receptors were also revealed that were absent at areas of distension-induced damage to the endothelium. These results suggest that endothelin-1 plays a role in vein graft failure, predominantly via the endothelin-A receptor.     

AdCMVCD／5FC自镣基因系统治疗CABG术后再狭窄

目的 研究胞嘧啶脱氨酶基因/5—氟胞嘧啶自杀基因系统对冠状动脉旁路移植术后再狭窄的治疗作用。 方法将含AdCMVCD的病毒上清加压注入兔颈外静脉管腔,半小时后剪下该静脉并用Cuff技术移植于兔颈动脉上,以单纯移植组和AdCMVLacz为对照,通过光镜和电镜观察平滑肌细胞的形态变化,并对血管桥外径、管腔、内膜、中膜面积和外弹力膜周长及管腔相对丧失率进行定量分析,以观察抑制内膜和中膜增生、防止血管再狭窄的效果。 结果 治疗组的内膜和中膜面积明显小于两个对照组;管腔丧失率亦明显减少,AdCMVCD组为3.68±0.42％,单纯移植组为9.68±0.41％.P<0.01。结论 AdCMVCD自杀基因系统对冠状动脉旁路移植术后再狭窄有明显的治疗作用。