全反式维甲酸对兔颈动脉粥样硬化病变中C-myc表达及血管平滑肌细胞增生的影响

Influence of all-trans retinoic acid on the expression of C-myc and the proliferation of vascular smooth muscle cells in carotid atherosclerosis in rabbits

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)及原癌基因C-myc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、ATRA治疗组,每组12只。手术组和治疗组均给予高脂饮食,2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,取病变血管应用苏木精-伊红染色、免疫组化和计算机图像分析法进行形态学、PCNA和C-myc表达水平的检测。结果①正常动脉壁未见PCNA及C-myc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C-myc表达水平增高;③治疗组C-myc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C-myc表达呈显著正相关(P<0.01)。结论ATRA可通过抑制C-myc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。

Purpose To investigate the influence of all-trans retinoic acid （ATRA） on the process of neointimal formation, vascular remodeling, the expression of C-myc in carotid atherosclerosis in rabbits. Methods Thirty-six New Zealand rabbits were randomly divided into 3 groups： normal group（n = 12）, control group（n = 12）, and ATRA-treated group（n = 12）. The last two groups were fed by high-cholesterol diet. Control and ATRA-treated group were made into carotid atherosclerosis model using air-drying after two weeks. ATRA-treated group were predosed with ATRA by gavage 3 days before surgery. All rabbits were killed one week and four weeks after surgery. After the target vessels were harvested,we used immunohistochemistry staining to measure the protein expression of C-myc and proliferation cell nuclear antigen PCNA. Meanwhile vessel morphological measurement were taken. Results ① In normal group, C-myc and PCNA were not detected. ② In control group, there were distinct neointima formation and narrow luminal area in six weeks and the expression of PCNA, C-myc are significantly high. ③ In ATRA-treated group, the expression of C-myc were significantly lower than in control group, ATRA-treated group had an outstanding smaller neointima/media area ratio and larger luminal area. ④The expression of PCNA and C-myc were in remarkable positive correlation. Conclusions Inhibiting VSMC proliferation by inhibiting the expression of C-myc may be one mechanism by which ATRA reduced neointima formation and elicited favorable geometric remodeling of the carotid atherosclerosis in rabbits.