白藜芦醇调节STIM1抗动脉粥样硬化的机制

Resveratrol Regulates STIM1 to Inhibit Atherosclerosis

目的:实验利用apoE^(-/-)小鼠高脂喂养建立动脉粥样硬化(atherosclerosis,AS)模型,观察基质相互作用因子1(stromal interaction molecule 1,STIM1)在白藜芦醇抗AS中的具体机制。方法:雌性apoE^(-/-)小鼠卵巢切除后高脂喂养建立AS模型,实验分为正常组、模型组、白藜芦醇低、中、高剂量(50,100,150 mg·kg^(-1))组及补充雌激素组(0.3 mg·kg^(-1))。分别检测各组小鼠血清中血脂4项,油红O染色观察胸主动脉形态改变,蛋白质免疫印迹(Western blot)分析各组小鼠血管组织中STIM1,钙释放激活钙通道蛋白1(Orai1)及雌激素受体α(ERα)蛋白表达,实时荧光定量聚合酶链式反应(Real-time PCR)分析各组小鼠血管组织中STIM1及Orai1 mRNA表达情况。结果:与正常组比较,模型组血清中总胆固醇(CHOL),甘油三酯(TG)及低密度脂蛋白胆固醇(LDL-C)升高,而高密度脂蛋白胆固醇(HDL-C)含量明显下降(P<0.05),给予白藜芦醇及雌激素后可明显降低高脂饮食所致的CHOL,TG及LDL-C明显升高,并可明显增加HDL-C含量(P<0.05)。油红O染色显示:正常组血管结构完整、清晰、内膜连续;模型组内膜增厚、可见明显脂质斑块;而加入不同剂量白藜芦醇或雌激素后,内膜增厚减轻且内膜下脂质斑块显著减少。Western blot及Real-time PCR结果显示:与正常组比较,模型组STIM1,Orai1蛋白及mRNA表达明显升高(P<0.05),而加入不同剂量白藜芦醇或雌激素后STIM1,Orai1蛋白及mRNA表达较模型组均明显下降(P<0.05);同时Western blot结果还显示,与模型组比较,加入不同剂量白藜芦醇或雌激素后均可增加血管组织中ERα表达。结论:白藜芦醇可通过增加ERα表达,下调STIM1及Orai1表达,抑制钙池操纵性钙通道(SOCC)介导的钙内流,延缓AS发生。

Objective：To study the protective mechanism of resveratrol on atherosclerosis through regulating stromal interaction molecule 1（STIM1）.Method：Atherosclerosis（AS） model was established by high-fat diet after ovariectomy in female apo E-/-mice,and then the mice were divided into normal control group,model group,resveratrol low,middle and high dose groups（50,100,150 mg·kg-1） and estradiol（E2） group.The lipid levels in the serum were detected.The changes of morphology in thoracic aorta were measured by oil Red O staining;the protein expression levels of STIM1,calcium release-activated calcium channel modulator 1（Orai1） and estrogen receptor α（ERα） in thoracic aorta were detected by Western blot;and the STIM1 and Orai1 mRNA expression levels were detected by Real-time PCR.Result：As compared with the normal group,the levels of total cholesterol（CHOL）,triglyceride（TG） and low density lipoprotein cholesterol（LDL-C） were significantly increased,while the level of high density lipoprotein cholesterol（HDL-C） was decreased significantly（P〈0.05） in model group;the levels of CHOL,TG and LDL-C were significantly decreased and the content of HDL-C was increased after the administration of resveratrol and estrogen（P〈0.05）.Oil red O staining showed that in normal control group,the vascular structure was integrated,clear,and the intima was continuous;in model group,the intima was obviously thick,with visible lipid plaques;while after treatment with resveratrol or estrogen,the thickness of intima and lipid plaques were reduced.Western blot and Real-time PCR results showed that as compared with the normal group,STIM1,Orai1 protein and mRNA expression levels were increased in model group model group（P〈0.05）,and were decreased after treatment with resveratrol or estrogen（P〈0.05）.In addition,ERα expression was increased after treatment with resveratrol or estrogen as compared with the model group.Conclusion：Resveratrol could delay the AS by up-regulating ERα,down-regulating the expression of STIM1 and Orai1 and inhibiting Ca2 ＋influx via SOCE.