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法舒地尔对大鼠颈动脉球囊损伤后血管内膜新生的抑制作用 被引量：3

Blockade of oxidative stress and Ras-MEK1/2-ERK1/2 pathway is involved in fasudil attenuating balloon injury-induced neointima hyperplasia
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摘要 目的研究法舒地尔对大鼠颈动脉球囊损伤后新生内膜的干预影响，并探讨可能的机制。方法30只雄性SD大鼠，随机分为5组：（1）假手术组：不做球囊损伤；（2）球囊损伤组仅作球囊损伤；（3）2．5mg组：球囊损伤后服法舒地尔2．5mg·kg-1·d-1；（4）5．0mg组：球囊损伤后服法舒地尔5．0mg·kg-1·d-1；（5）10mg组：球囊损伤后口服法舒地尔10．0mg·kg-1·d-1。14d后光镜和苏木精-伊红染色法（HE）染色观察新生内膜的内膜中膜比值；以免疫组化方法检测增殖细胞核抗原（PCNA）的表达，并计算积分光吸光度（IA）；酶联免疫吸附（ELISA）法测定组织中氧化应激标志物8-羟基脱氧鸟苷（8-OHdG）和丙二醛（MDA）的水平。用免疫印迹（Western blot）法测定磷酸化和非磷酸化的Ras、丝裂原活化蛋白激酶（MEK1／2）、细胞外调节蛋白激酶（ERK1／2）的蛋白表达。结果与假手术组血管内膜与中膜比值（0．22±0．01）比较，球囊损伤组新生内膜明显增生（2．71±0．23）；与球囊损伤组相比较，法舒地尔2．5mg组（1．72±0．24）、5．0mg组（1．23±0．11）、10．0mg组（0．85±0．12）呈剂量依赖抑制新生内膜的增殖，差异有统计学意义（F=767．3，P〈0．01）。法舒地尔以剂量依赖形式抑制PCNA的表达，IA值球囊损伤组为（53．42±2．30），与2．5mg（45．25±1．62）、5．0mg组（22．55±0．88）、10．0mg组（19．61±0．79）比较，差异有统计学意义（均P〈0．01）。氧化应激标志物8-OHdG、MDA法舒地尔干预各组与球囊损伤组比较下降，差异有统计学意义（均P〈0．01）；与球囊损伤组Ras表达0．62±0．10比较，法舒地尔干预各组剂量由低至高依次为0．49±0．12、0．39±0．13、0．20±0．23，差异有统计学意义（P〈0．05或P〈0．01）；球囊损伤组MEK1／2为0．56±0．10、ERK1／2为0．64±0．13，法舒地尔干预各组剂量由低至高依次为0．35±0．14、0．29±0．09、0．11±0．12与0．48±0．15，0．32±0．08，0．12±0．09，差异有统计学意义（P〈0．05或P〈0．01），法舒地尔抑制Ras磷酸化的MEK1／2、ERK1／2的蛋白表达。结论法舒地尔通过抑制氧化应激和失活Ras—MEK1／2ERK1／2通路抑制大鼠颈动脉球囊损伤后再狭窄形成。 Objective To evaluate the effects of fasudil on neointima hyperplasia in rat carotid artery balloon-injury model, and explore the potential molecular mechanisms of this effect. Methods Totally 30 male Sprague-Dawley （SD） rats were randomly divided into sham-operation group, balloon injury group, 2.5 ml/kg fasudil intervention group, 5 ml/kg fasudil intervention group, 10 ml/kg fasudil intervention group. The intima-to-media（I/M） area ratio of neointima was calculated at 14th day after operation; the protein expression of proliferating cell nuclear antigen（PCNA） was measured by immunohistochemical and the integrated optical density （IA） was calculated. As the marker of oxidative stress, the levels of 8-hydroxy-2＇-deoxyguanosine （8-OHdG） and malondialdehyde （MDA） were measured by enzyme-linked immunosorbent assay （ELISA）. The expressions of pbosphorylated and non-pbosphorylated Ras, mitogen activated protein kinase kinase （MEK1/2） and extracellular signal regulated kinase （ERK1/2） were measured by Western blot. Results The I/M ratios were（0.22 ± 0. 01） in sham-operation group, （2.71 ± 0.23） in balloon injury group, （1.72 ± 0.24）in 2.5 ml/kg fasudil intervention group, （1.23 ± 0.11）in 5 ml/kg fasudil intervention group, （0.85±0.12）in 10 ml/kg fasudil intervention group. As compared with sham operation group, I/M area ratio was increased in balloon-injury group, and three fasudil intervention group inhibited neointima hyperplasia in a dose-dependent manner （all P〈 0.01）. The IA indexes were （15.11± 1.42）,（53.42±2.30）,（45.25±1.62）,（22.55±0.88） and（19.61±0.79） in the above five groups, respectively, showing the fasudil inhibited PCNA expression （all P〈0.01） . Fasudil also inhibited the levels of 8-OHdG and MDA in a dose-dependent manner [8-OHdG.. （54.34±4.50）ug/kg, （106.81 ± 6.67） ug/kg, （94.21 ± 3.34 ）ug/kg, （65.58 ± 5.13 ）ug/kg, （51.32 ± 2.34 ）ug/kg ; MDA： （19.94 ± 0.65）umol/kg, （58.83±2.81）umol/kg, （48.94±1.35）umol/kg, （40.62±3.24）umol/kg, （36.85± 0.91 ）umol/kg （all P〈0.01）]. Compared with balloon injury group, the relative expressions of Ras in three fasudil intervention group were 0. 49±0.12,0. 39±0.13, 0. 20±0. 23 vs. 0. 62±0.10（P〈0.05 or,P〈0.01）; MEK1/2 0.35 ±0.14, 0.29±0.09, 0.11±0.12 vs. 0.56±0.1（P〈0.05 or,P〈 0.01）; ERK1/2 0.48±0.15,0.32 ±0.08,0.12±0.09 vs. 0.64±0.13（P〈0.05 or,P〈0.01）. The activations of ERK1/2, MEK1/2 and Ras were strongly suppressed in fasudil treated samples on day 14 after balloon injury. Conclusions Blockade of oxidative stress and Ras-MEK1/2-ERK1/2 pathway is involved in the fasudil attenuating of balloon injury-induced neointima hyperplasia
作者 陈亚丽
机构地区 河北医科大学第三医院心血管一科
出处 《中华老年医学杂志》 CAS CSCD 北大核心 2012年第9期814-818,共5页 Chinese Journal of Geriatrics
关键词 氧化性应激 颈动脉损伤 血管内膜 Oxidative stress Carotid artery injures Tunica intima
分类号 R285.5 [医药卫生—中药学]
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共引文献8

同被引文献17

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中华老年医学杂志
2012年 第9期

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