单纯球囊扩张与支架源性冠状动脉内膜增生程度的比较及相关因素

经皮腔内冠状动脉成形术(PTCA)后再狭窄的防治是PTCA的当务之急.新生内膜增生既是导致支架内再狭窄的主要原因,也是导致球囊PTCA后再狭窄的原因之一.动物实验,显示支架置入后内膜的增生远较单纯球囊扩张显著,并可能与血管损伤和炎症反应有关.     

冠状动脉内超声评价支架再狭窄

目的探讨冠状动脉内支架再狭窄的机制.方法50例确诊冠心病患者接受65个支架置入术,10个月后复查冠状动脉造影和血管内超声成像检查.根据冠状动脉造影结果将患者分为支架再狭窄组(26个支架)和无支架再狭窄组(39个支架),分别对其冠状动脉造影和血管内超声进行定量测量分析.同时观察支架内再狭窄的方式.结果血管内超声定量测量发现支架再狭窄组最小血管内膜腔面积和支架最小截面积[分别为(2.5±1.2)mm2和(4.2±1.8)mm2]明显小于无支架再狭窄组[分别为(5.2±1.4)mm2和(6.8±1.7)mm2](P分别＜0.001和＜0.01),但两组新生内膜截面积比较差异无显著性[分别为(1.7±1.0)mm2和(1.5±0.9)mm2,P＞O.05].支架内再狭窄以局灶性狭窄为多见(69.2%).结论支架扩张程度是决定支架内再狭窄的重要因素,而支架内内膜增生并不明显.支架内再狭窄以局灶性狭窄为多见.     

药物涂层支架--介入心脏病学的突破性进展

经皮冠状动脉腔内成形术 (PTCA)和支架置入术后的最突出问题是术后 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 ,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 ,通过血管平滑肌细胞 (VSMC)受体 ,使平滑肌细胞分裂 ,导致平滑肌细胞增生、基质分泌并向内膜迁移 ,使新生内膜过度增生 ,…     

单纯球囊扩张与支架源性冠状动脉内膜增生程度的比较及相关因素

经皮腔内冠状动脉成形术（PTCA）后再狭窄的防治是PTCA的当务之急。新生内膜增生既是导致支架内再狭窄的主要原因，也是导致球囊PTCA后再狭窄的原因之一。动物实验，显示支架置入后内膜的增生远较单纯球囊扩张显著，并可能与血管损伤和炎症反应有关。     

支架内新生动脉粥样硬化研究进展

经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)彻底改变了冠心病的治疗方法。药物洗脱支架(drug-eluting stent,DES)则进一步成功地解决了早期支架内新生内膜过度生长的问题,降低了晚期血栓事件的风险,改善了患者的预后。然而,由于强大的抗内膜增生药物的影响,血管愈合时间大大延迟,包括晚期支架内血栓形成和晚期支架内再狭窄在内的晚期支架失败仍然是一个值得关注的问题,而越来越多的影像学及病理学证据表明,支架内新生动脉粥样硬化(in-stent neoatherosclerosis,ISNA)是导致晚期支架失败的重要原因。本文旨在从ISNA的流行病学、形态学特征、潜在机制等方面作一综述。     

剪切力与支架内再狭窄

研究表明支架内再狭窄主要由内膜增生、边缘重构和炎症反应等引起。边缘重构对支架内再狭窄与非支架内再狭窄的主要区别在于剪切力的不同。而剪切力能对内皮细胞的形态和功能产生影响。因此,剪切力、内皮细胞和支架内再狭窄三者关系密切。     

生物可吸收支架的前景与挑战

支架置入术是目前广泛应用的冠心病治疗手段,可成功恢复血管血运,但再狭窄一直影响着远期效果,血管内膜过度增生是主要原因。药物洗脱支架预防再狭窄的同时也存在着诸多不足,最突出的是晚期血栓形成。新生内膜增生过度导致的再狭窄,与支架涂层药物对正常内皮细胞的非特异性抑制导致的晚期血栓形成,是支架置入术面临的主要矛盾。生物可吸收支架,包括可吸收聚合物支架以及可吸收金属支架,有望解决这一难题,应用前景十分广阔。     

双抗支架联合内皮祖细胞移植防治支架内晚期再狭窄

目的：探讨双抗-[CD34、血管内皮生长因子受体（VEGFR）-2]支架联合局部移植内皮祖细胞（EPCs）防治血管支架内晚期再狭窄的效果.方法：以反复浸泡吹干法制备双抗支架.兔动脉粥样硬化模型建立后动脉内置入药物涂层支架（药物涂层支架组,8只）或双抗支架＋ EPCs移植（双抗支架组,8只）.随访2月.观察管腔最狭窄百分比、支架内血管新生内膜增生.结果：与药物涂层支架组比较,双抗支架组支架内管腔面积狭窄百分比[（28.3±4.2）％比（8.8±1.45）％]、血管新生内膜面积[（1.44±0.34）m2比（0.46±0.21） m2]、最大内膜厚度[（172±5.0）μmm比（105±4.9）μmm]明显减少（P均＜0.05）.结论：双抗支架＋EPCs移植可显著降低支架内晚期再狭窄.     

辛伐他丁对支架新生内膜的作用

目的观察他丁类调脂药物对支架再狭窄和支架内新生内膜的影响.方法对单支冠脉病变行支架植入术的患者随机接受或不接受调脂药物的治疗,10月后复查冠脉造影和血管内超声检查.结果 65位患者随机接受辛伐他丁10mg治疗.辛伐他丁组患者在接受降脂治疗后血清总胆固醇降低15%,低密度脂蛋白胆固醇下降了26%,高密度脂蛋白胆固醇增加12%.辛伐他丁组和对照组支架再狭窄率无差异(分别为30.3%和37.5%,P>0.05).定量冠脉造影结果两组比较,两组参考段血管直径、支架最小管腔直径以及直径狭窄率均无明显差异.血管内超声发现辛伐他丁组参考段血管内膜腔截面积、最小血管内膜腔截面积以及最小支架截面积均无显著性差异.新生内膜截面积两组比较对照组大于辛伐他丁组,但无统计学意义.结论辛伐他丁长期治疗能够有效降低血中致动脉粥样硬化的脂蛋白.但10 mg/日的辛伐他丁对支架的再狭窄率以及支架内膜增生无明显影响.     

雷帕酶素和巴曲酶复合药物涂层支架预防支架内再狭窄的实验研究

目的评价裸支架、巴曲酶支架、雷帕酶素支架、雷帕酶素和巴曲酶复合药物涂层支架（rapamycin-batroxobin eluting stent,RBES）抑制内膜增生的作用以及预防支架内再狭窄的效果。方法采用微喷法制备雷帕酶素和巴曲酶复合药物涂层支架,将裸支架、巴曲酶支架和雷帕酶素支架做为对照,复合药物组减少术后服用氯吡格雷的剂量和时间。于支架置入后3、7、28d截取支架段血管连同邻近的近端正常血管段,通过病理组织学分析和聚合酶链反应技术检测支架局部内膜增生情况。结果复合药物支架、雷帕酶素支架在再狭窄率、冠脉狭窄程度、管腔面积、新生内膜面积方面与裸支架组、巴曲酶支架组有显著差异（P<0.05）。复合药物支架组与雷帕酶素组在再狭窄率、冠脉狭窄程度、管腔面积、新生内膜面积方面无显著差异。裸支架组、巴曲酶支架组在再狭窄率、冠脉狭窄程度、管腔面积、新生内膜面积方面无显著差异。正常血管段在各个时间段增殖细胞核抗原（PCNA）mRNA均呈现无明显差异的低表达。裸支架、巴曲酶支架、雷帕酶素支架和复合药物支架置入后3d局部血管壁PCNA mRNA即呈现高表达,裸支架、巴曲酶支架显著高于正常血管段。雷帕酶素支架和复合药物支架略高于正常血管段,显著低于裸支架、巴曲酶支架,巴曲酶支架略低于裸支架;复合支架略低于雷帕酶素支架。结论复合药物支架置入可在一定程度上抑制内膜的增生反应,预防支架内再狭窄。     

Rho-kinase is an important therapeutic target in cardiovascular medicine

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.     

Stent implantation activates RhoA in human arteries: inhibitory effect of rapamycin

In-stent restenosis is a novel pathobiologic process resulting from vascular smooth muscle cell (VSMC) proliferation, migration and excessive matrix production. The present study was designed to assess the activity of RhoA, a major regulator of VSMC proliferation and migration, after stenting and to determine its role in the neointimal formation. Analysis of RhoA activity in an ex vivo organ culture model of human internal mammary arteries demonstrates that stenting induced a time-dependent increase in RhoA activity (4.9 +/- 0.4 vs. 1.2 +/- 0.2 in control at 28 days, n = 4, p < 0.0001) associated with a concomitant decrease in p27 expression. Treatment of stented arteries with the permeant RhoA inhibitor TAT-C3 (10 microg/ml) or Rho-kinase inhibitors (Y-27632, 10 micromol/l; fasudil, 10 micromol/l) inhibited both neointimal formation and decrease in p27 expression. Rapamycin (1 and 10 nmol/l) also inhibited neointimal formation, and induced a loss of RhoA expression. The inhibitory effect of rapamycin on neointimal thickening is prevented by the dominant active form of RhoA. Our study shows that stent implantation induces maintained RhoA activation and demonstrates that the inhibitory action of rapamycin on RhoA expression plays a key role in its antirestenotic effect.     

Role of Rho-associated kinase in neointima formation after vascular injury

BACKGROUND: The Rho/Rho-associated kinase (Rho-kinase) system is implicated in various cellular functions, including migration, proliferation, and apoptosis. Because a possible role of the system is suggested in neointima formation after vascular injury, we sought to examine whether a new specific Rho-kinase inhibitor, Y27632, prevents neointima formation of the balloon-injured rat carotid artery, and if so, to investigate the effects of Y27632 on migration, proliferation, and apoptosis of smooth muscle cells (SMCs) in the injured artery. METHODS AND RESULTS: Y27632 was administered intraperitoneally from 1 day before to 14 days after vascular injury. Treatment with Y27632 inhibited phenylephrine-induced Rho-kinase activation in the carotid artery on the basis of immunoblotting against the phosphorylated myosin-binding subunit of myosin phosphatase. Y27632 markedly prevented neointima formation at days 7 and 14. In controls, BrdU(+) proliferating and TUNEL(+) apoptotic SMCs were transiently and coincidentally increased in the neointima, with a peak at day 7. Y27632 significantly increased the neointimal TUNEL(+) SMCs at days 7 and 14, but not BrdU(+) SMCs. Y27642 significantly decreased the number of intimal SMCs at day 4, while not affecting the number of BrdU(+) or TUNEL(+) SMCs. Reendothelialization after balloon injury was not significantly affected by Y27632 at days 7 and 14. CONCLUSIONS: Y27632 inhibited neointima formation by enhancing SMC apoptosis and probably by suppressing early SMC migration. Therefore, a role of Rho-kinase is suggested in neointima formation after vascular injury.     

Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats

Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.     

黄连素对血管平滑肌细胞增殖、大鼠颈动脉球囊损伤模型及PTEN基因表达的影响

目的:探讨黄连素对血管平滑肌细胞(VSMC)增殖、大鼠颈动脉球囊损伤后动脉新生内膜形成及损伤后再狭窄的影响,及其影响是否通过改变PTEN(第10q23染色体的抑癌基因)的表达来实现。方法:MTT法检测黄连素对主动脉VSMC增殖的影响,实时定量RT-PCR及Western blot法测定黄连素对VSMC PTEN在转录及蛋白水平表达的影响。建立颈动脉球囊损伤模型,观察黄连素对新生内膜形成及再狭窄的影响及血管组织表达PTEN的变化。结果:黄连素抑制大鼠主动脉VSMC的增殖,改善损伤血管新生内膜形成及再狭窄;上调PTEN表达,且与浓度呈正相关,200μmol/L黄连素干预VSMC效果最佳;球囊损伤模型再狭窄的预防经过术前、术后各2周的黄连素处理,较单纯术后黄连素处理效果更佳。结论:黄连素可能通过上调PTEN表达来抑制VSMC增殖与球囊损伤模型内膜的增生及损伤后再狭窄。     

Inhibitory effects of novel AP-1 decoy oligodeoxynucleotides on vascular smooth muscle cell proliferation in vitro and neointimal formation in vivo

Excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation are critical steps in the pathogenesis of atherosclerosis and restenosis after percutaneous transluminal angioplasty. In this study, we investigated the hypothesis that the activator protein-1 (AP-1) plays an important role in neointimal formation after vascular injury. A circular dumbbell AP-1 decoy oligodeoxynucleotide (CDODN) was developed as a novel therapeutic strategy for restenosis after angioplasty. This CDODN was more stable than the conventional phosphorothioate linear decoy ODN (PSODN) and maintained structural integrity on exposure to exonuclease III or serum. Transfection with AP-1 decoy ODNs strongly inhibited VSMC proliferation and migration, as well as glucose- and serum-induced expression of PCNA and cyclin A genes. Administration of AP-1 decoy ODNs in vivo using the hemagglutinating virus of Japan (HVJ)-liposome method virtually abolished neointimal formation after balloon injury to the rat carotid artery. Compared with PSODN, CDODN was more effective in inhibiting the proliferation of VSMCs in vitro and neointimal formation in vivo. Our results collectively indicate that AP-1 activation is crucial for the mediation of VSMC proliferation in response to vascular injury. Moreover, the use of stable CDODN specific for AP-1 activity in combination with the highly effective HVJ-liposome method provides a novel potential therapeutic strategy for the prevention of restenosis after angioplasty in humans.     

非对称性二甲基精氨酸通过Rho／ROCK信号通路介导大鼠血管平滑肌细胞迁移

目的探讨非对称性二甲基精氨酸（Asymmetric Dimethylarginine,ADMA）对血管平滑肌细胞（vascular smooth muscle cells,VSMCs）迁移和形态变化的影响,并探索Rho／ROCK和MAPK信号转导通路在其中的作用。方法原代培养大鼠VSMCs,并通过转染二甲基精氨酸二甲胺水解酶hDDAH2过表达载体,L-精氨酸（1mM）或ROCK抑制剂Y27632等预处理,观察细胞RhoA蛋白与底物rhotekin蛋白结合程度,ROCK底物MYPT-1磷酸化程度、VSMC迁移能力和细胞骨架及黏着斑定位情况。结果（1）ADMA诱导平滑肌细胞Rho/OCK信号转导通路;（2）Rho/OCK和ERK信号通路交联介导ADMA对平滑肌细胞迁移能力的诱导作用;（3）ADMA通过Rho/OCK诱导平滑肌细胞骨架无序排列、黏着斑定位改变;（4）L-精氨酸对上述变化有逆转作用。结论ADMA通过Rho/OCK和ERKl／2信号交联诱导VSMC迁移和表型转化,而L-精氨酸逆转ADMA引起的改变。     

Rosuvastatin regulates vascular smooth muscle cell phenotypic modulation in vascular remodeling: role for the urokinase receptor

The urokinase (uPA)/urokinase receptor (uPAR) multifunctional system is an important mediator of migration and proliferation of vascular smooth muscle cells (VSMC). However, whether uPA/uPAR-directed mechanisms are involved in the beneficial effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on vascular remodeling remains unexplored. In this study, we have investigated the effect of the hydrophilic statin rosuvastatin on neointimal remodeling, and the role of uPAR. Using an ex vivo organ and in vitro cell culture models we demonstrate that rosuvastatin decreases injury-induced neointima formation and proliferation of medial VSMC in porcine coronary arteries, as well as migration and proliferation of human coronary VSMC. Studies on the underlying mechanisms show that rosuvastatin impairs VSMC transition from their physiological contractile to the pathophysiological synthetic phenotype. These effects are mediated, at least in part, via uPAR, as confirmed by means of rosuvastatin-directed uPAR expression and uPAR silencing in both models. Our findings provide evidence that rosuvastatin modulates VSMC phenotypic changes and subsequently their proliferation and migration, and indicate the important role for uPAR in these processes. This mechanism contributes to the beneficial non-lipid lowering effect of rosuvastatin on negative vascular remodeling.     

Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo

We have previously shown that long-term treatment with an inflammatory cytokine from the adventitia causes the development of coronary vascular lesions, with the accumulation of macrophages. Recent studies in vitro have suggested that small G-protein Rho and its effector, Rho-kinase/ROK/ROCK, may be the key molecules for various cellular functions, including cell adhesion and movement. In this study, we examined whether adventitia-derived macrophages cause the formation of coronary vascular lesions in vivo and, if so, whether Rho-kinase is involved in the process. Porcine coronary segments from the adventitia were chronically treated with monocyte chemoattractant protein-1 alone, oxidized low density lipoprotein alone, or both. Vascular lesion formation (neointimal formation and development of vascular remodeling) was mostly enhanced at the coronary segment cotreated with monocyte chemoattractant protein-1 and oxidized low density lipoprotein, where the phosphorylation of myosin binding subunit of myosin phosphatase was increased, indicating an increased activity of Rho-kinase in vivo. Histological examination demonstrated that macrophages were accumulated at the adventitia and thereafter migrated into the vascular wall. Long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor (hydroxyfasudil) after oral absorption, markedly inhibited the myosin binding subunit phosphorylation, the macrophage accumulation and migration, and the coronary lesion formation in vivo. These results indicate that Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in our porcine model in vivo.     

Rho/Rho激酶信号通路与冠心病

Rho/Rho激酶信号通路是体内普通存在的一条信号转导通路,它通过调节细胞内肌动蛋白骨架的聚合状态参与多种细胞功能,包括细胞收缩、迁移、黏附、增殖、凋亡及基因表达等。Rho/Rho激酶信号通路的异常激活在冠心病的发病机制和病理生理中发挥了重要作用,对此信号转导通路的研究可以为冠心病的预防和治疗提供新的靶点。现就Rho/Rho激酶信号通路的特征及其与冠心病的关系作一综述。