目的 探討纈沙坦對頸動脈粥樣硬化大鼠血管緊張素Ⅱ 1型受體（AT1R）/磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/哺乳動物雷帕霉素靶蛋白（mTOR）通路及血管內(nèi)皮細(xì)胞自噬的影響。方法 采用高脂飼料飼喂結(jié)合頸動脈球囊損傷法制備頸動脈粥樣硬化大鼠模型，隨機(jī)分為模型組（生理鹽水），纈沙坦低、中、高（10、20、30 mg/kg）劑量組和陽性對照組（阿托伐他汀，2.5 mg/kg），另取假手術(shù)大鼠作為對照組（生理鹽水），每組15只，均每天ig給藥1次，連續(xù)4周，給藥體積10 mL/kg。末次給藥結(jié)束24 h后，全自動生化分析儀檢測各組大鼠血脂水平，包括總膽固醇（TC）、三酰甘油（TG）、低密度脂蛋白膽固醇（LDL-C）和高密度脂蛋白膽固醇（HDL-C）；酶聯(lián)免疫吸附（ELISA）法檢測各組大鼠頸動脈血清中白細(xì)胞介素6（IL-6）、白細(xì)胞介素1β（IL-1β）和腫瘤壞死因子α（TNF-α）水平；蘇木精-伊紅（HE）染色觀察各組大鼠頸動脈內(nèi)皮組織病理學(xué)變化；單丹磺酰尸胺（MDC）染色法檢測各組大鼠頸動脈內(nèi)皮細(xì)胞自噬率；蛋白免疫印跡（Western blotting）法檢測各組大鼠自噬標(biāo)記蛋白LC3-Ⅱ、Beclin 1和通路蛋白AT1R表達(dá)水平及PI3K、Akt、mTOR磷酸化水平。結(jié)果 與對照組相比，模型組大鼠頸動脈組織內(nèi)皮細(xì)胞排列紊亂，內(nèi)皮破損，大量炎性因子浸潤，TC、TG、LDL-C、IL-1β、TNF-α、IL-6水平及AT1R蛋白表達(dá)和PI3K、Akt、mTOR磷酸化水平顯著升高（P<0.05），HDL-C水平、細(xì)胞自噬率、LC3-Ⅱ和Beclin 1蛋白表達(dá)水平顯著降低（P<0.05）；與模型組相比，纈沙坦低、中、高劑量組大鼠頸動脈組織中內(nèi)膜逐漸平滑，炎性因子浸潤依次減少，TC、TG、LDL-C、IL-1β、TNF-α、IL-6水平及AT1R蛋白表達(dá)和PI3K、Akt、mTOR磷酸化水平依次降低（P<0.05），HDL水平、細(xì)胞自噬率、LC3-Ⅱ和Beclin 1蛋白表達(dá)水平顯著升高（P<0.05）；纈沙坦高劑量組與陽性對照組大鼠各項指標(biāo)差異無統(tǒng)計學(xué)意義。結(jié)論 纈沙坦可能通過下調(diào)AT1R/PI3K/AKT/mTOR信號通路，提高LC3-Ⅱ和Beclin 1自噬相關(guān)蛋白表達(dá)水平，促進(jìn)頸動脈粥樣硬化大鼠血管內(nèi)皮細(xì)胞自噬，減輕炎癥反應(yīng)。

Objective To investigate the effects of valsartan on angiotensin Ⅱ type 1 receptor (AT1R)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and the autophagy of vascular endothelial cells in carotid atherosclerosis rats. Methods The rat models of carotid atherosclerosis were established by high-fat diet combined with carotid balloon injury. The rats were randomly divided into model group (normal saline), low (10 mg/kg), medium (20 mg/kg), high (30 mg/kg) valsartan groups and positive control group (atorvastatin, 2.5 mg/kg), the sham operated rats were taken as the control group (normal saline), with 15 in each group, the drug was given by intragastric administration once a day for 4 weeks, with a volume of 10 mL/kg. At 24 hours after the last administration, the blood lipid levels of rats in each group were detected by automatic biochemical analyzer, including total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The levels of interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin eosin (HE) staining was used to observe the pathological changes of carotid artery endothelium. The autophagy rate of carotid artery endothelial cells was detected by MDC staining. Western blotting was used to detect the expression levels of autophagy marker proteins LC3-Ⅱ, Beclin 1, AT1R and phosphorylation levels of PI3K, Akt and mTOR. Results Compared with those in the control group, the endothelial cells of carotid artery in the model group were disorderly arranged, the endothelium was damaged and a large number of inflammatory factors were infiltrated, and TC, TG, LDL-C, IL-1β, TNF-α, IL-6 levels, AT1R protein expression and PI3K, Akt, mTOR phosphorylation levels were significantly higher (P<0.05), HDL-C level, autophagy rate, LC3-Ⅱ and Beclin 1 protein expression levels were significantly lower (P<0.05). Compared with those in the model group, the intima of carotid artery in the low, medium and high dose valsartan groups gradually smoothed, and the infiltration of inflammatory factors decreased in turn. TC, TG, LDL-C, IL-1β, TNF-α, IL-6 levels, AT1R protein expression and PI3K, Akt, mTOR phosphorylation levels decreased in turn (P<0.05). HDL level, autophagy rate, LC3-Ⅱ and Beclin 1 protein expression levels were significantly higher (P<0.05). There was no significant difference between the high dose valsartan group and the positive control group. Conclusions Valsartan may increase the expression levels of LC3-Ⅱ and Beclin 1 autophagy related proteins by down-regulating AT1R/PI3K/Akt/mTOR signaling pathway, promote the autophagy of vascular endothelial cells in carotid atherosclerosis rats, and reduce the inflammatory reaction.

R966

河南省醫(yī)藥衛(wèi)生計劃項目（182102310159）