固醇调节素结合蛋白调节辛伐他汀对血管平滑肌细胞的作用

Effects of simvastatin on vascular smooth muscle cells regulated by steroi regulatory element binding proteins

目的观察辛伐他汀对血管平滑肌细胞(VSMCs)是否存在双向作用,是否通过固醇调节素结合蛋白(SREBPs)调节起作用。方法①培养大鼠原代VSMCs,观察不同浓度辛伐他汀对VSMCs增殖、迁移的影响,以及SREBP-1、SREBP-2 mRNA在VSMCs的表达。②建立大鼠动脉粥样硬化血管损伤模型,分为动脉粥样硬化损伤组(n=6)、低剂量辛伐他汀组(n=6)和高剂量辛伐他汀组(n=6);另设正常对照(假手术)组(n=8)。低剂量和高剂量辛伐他汀组每天1次灌胃给药,剂量分别为0.5 mg·kg^(-1)·d^(-1)和2.5 mg·kg^(-1)·d^(-1),正常对照组和动脉粥样硬化损伤组喂予等量生理盐水,4周后处死动物。酶法测定各组血脂水平,检测胸主动脉和左颈总动脉内膜/(内膜+中膜)比值。RT-PCR法检测SREBP-1、SREBP-2 mRNA在血管的表达。结果细胞及动物实验均证明辛伐他汀对VSMCs增殖和迁移无双向调节作用。低剂量辛伐他汀对VSMCs的增殖和迁移无促进作用,高剂量辛伐他汀抑制VSMCs增殖和迁移,且这种作用呈剂量依赖性但不依赖他汀的调脂性。辛伐他汀能激活VSMCs的SREBP-1、SREBP-2 mRNA表达,且高浓度辛伐他汀SREBP-1、SREBP-2 mRNA表达显著。结论辛伐他汀可能通过激活SREBPs抑制血管平滑肌细胞增殖和迁移。

Objective To explore the biphasic effects of simvastatin on vascular smooth muscle cells （VSMCs）, which were regulated by sterol regulatory element binding proteins （SREBPs）. Methods （1） Rat primary VSMCs were cultured, the effects of different concentrations of simvastatin on proliferation and migration of VSMCs were observed, and the expression of SREBP-1 and SREBP-2 mRNA on VSMCs was detected. （2）Rat models of atherosclerosis were established, and were divided into atherosclerotic injured group （ n = 6）, low concentration simvastatin group （n = 6） and high concentration simvastatin group （n = 6）. Besides, normal control group （sham operation group, n = 8）was established. Intragastricadministration of simvastation of 0.5 mg kg^1· d^-1 and 2.5 mg kg^1· d^-1 was conducted in low concentration simvastatin group and high concentration simvastation group, respectively, while those in normal control group and atherosclerotic injured group were given same amount of normal saline. Rats were sacrificed 4 weeks later. Plasma lipid levels were examined by enzymic method, ratios of intima/（intima ＋ tunica media） of thoracic aorta and left common carotid arterywere determined, and the expression of SREBP-1 and SREBP-2 mRNA on blood vessels was detected by RT-PCR. Results Simvastatin didn＇t show biphasic effects on the proliferation and migration of VSMCs. Low concentration simvastatin didn＇t promote the proliferation and migration of VSMCs, while high concentration simvastatin showed inhibition effect on the proliferation and migration of VSMCs, which was dose-dependent and independent of lipid regulation effect by simvastatin. Simvastatin could activate the expression of SREBP-1 and SREBP-2 mRNA of VSMCs. Moreover, high concentration simvastatin could significantly activate the expression of SREBP-1 and SREBP-2 mRNA. Conclusion Simvastatin can inhibit the proliferation and migration of VSMCs by activating SREBPs.