4-苯基丁酸抑制蛋白激酶R样内质网激酶信号通路对大鼠肺动脉高压的作用  

Effect of 4-phenylbutyric acid on pulmonary arterial hypertension by inhibition of protein kinase R like endoplasmic reticulum eIF2 kinase signal pathway in rats

作　　者：武云[1] 王捷[2] 李倩[1] 李康[3] 阿里旦.艾尔肯 古丽那扎尔[1] 吴雷琪[1] 米娜瓦尔.胡加艾合买提 

机构地区：[1]新疆医科大学第一附属医院全科医学科,乌鲁木齐830054 [2]新疆医科大学第一附属医院药学部,乌鲁木齐830054 [3]新疆医科大学成教学院,乌鲁木齐830011

出　　处：《中国临床药理学杂志》2016年第23期2161-2165,共5页The Chinese Journal of Clinical Pharmacology

基　　金：新疆医科大学第一附属医院自然科学基金青年基金资助项目(2013ZRQN03)

摘　　要：目的通过4-苯基丁酸(4-PBA)对内质网应激关键信号通路蛋白激酶R样内质网激酶(PERK)的干预,探讨其对大鼠肺动脉高压的作用。方法选择Wistar雄性大鼠,按照体重随机分为正常组、模型组、实验1组及实验2组。用一次性腹腔注射野百合碱(60 mg·kg^(-1))的方法建立肺动脉高压模型。实验1组于建模2周后,按500 mg·kg^(-1)·d-1剂量给大鼠灌服4-PBA 2周;实验2组于建模第1天开始,每日按同等剂量给大鼠灌服4-PBA 4周。分别用BL-420F生物信息采集系统、HE染色及分子生物学手段检测各组大鼠血流动力学、病理形态学及PERK信号通路中关键因子的mRNA水平及蛋白表达。结果经4-PBA干预后,与模型组的平均肺动脉压力为(57.10±4.77)mm Hg相比,实验1组及实验2组的平均肺动脉压力分别为(23.06±1.54),(37.31±4.57)mm Hg,显著降低,差异有统计学意义(P<0.001)。与模型组的肺细小动脉中膜厚度比率为(50.84±6.12)%相比,实验1组及实验2组的肺细小动脉中膜厚度比率分别为(22.05±4.86)%,(18.36±1.51)%,明显降低,差异有统计学意义(P<0.001)。PERK信号通路中关键因子Perk的mRNA水平:模型组为21.93±5.71,实验1组及实验2组分别为1.02±0.05,4.01±0.27,明显降低,差异有统计学意义(P<0.01);同时,模型组的蛋白表达水平为0.48±0.04,实验1组及实验2组分别为0.32±0.04,0.24±0.03,明显降低,差异有统计学意义(均P<0.01);其余因子的mRNA及蛋白表达水平较模型组降低,差异有统计学意义(P<0.05)。结论 4-PBA通过抑制内质网应激关键信号通路PERK,可以达到防治肺动脉高压的作用。Objective To investigate the effects of 4 - phenylbutyric acid （4 -PBA） on pulmonary arterial hypertension （PAH） by PKR like en- doplasmic reticulum eIF2 kinase （PERK） signal pathway in rats. Methods Male Wistar rats were randomly divided into four groups： nor- mal group, model group, experimatal- 1 group （reversal） and a experi- matal -2 group （prevention）. The rat was intraperitoneal injection mono- crotaline （60 mg · kg^- 1 ） for establish models. The rats in experimatal - 1 group accepted 500 mg · kg^- 1 . d^-1 4 - PBA starting on the third week of model induction and continuing for 2 weeks. The rats in experimatal -2 group accepted 500 mg · kg^-1· d^-1 4 -PBA starting on the day of model induction and continuing for 4 weeks. The parameters of hemodynamics,pathology and molecular biology were tested by BL -420F biological and functional information collection system, He- matoxylin -Eosin staining, quantitative real -time PCR analysis and Western blot analysis after 4 weeks administration in 4 groups. Results After rats accepted 4 - PBA, the extent of mean pulmonary artery pressure in model group was （57.10 ± 4. 77 ） mmHg. Compared with the model group, the extent of mean pulmonary artery pressure in experimatal - 1 group and a experimatal - 2 group were （23.06± 1.54）, （ 37.31 ± 4. 57 ） mmHg with statistical differ- ence （ both P 〈 0. 001 ）. The ratio of medial wall thickness in model group was （50. 84 ± 6. 12 ） %. Compared with the model group, the ratio of medial wall thickness in experimatal - 1 group and a experimatal - 2 group were （22.05 ± 4. 86） %, （ 18.36 ± 1.51 ） % with statistical difference （ both P 〈 O. O01 ）. The mRNA levels of Perk in model group was 21.93 ± 5.71. Compared with the model group, the mRNA levels of Perk in experimatal - 1 group and a experimatal -2 group were 1.02 ±0. 05, 4. 01±0. 27 with statistical difference（both P 〈0. 01 ）. The protein levels of Perk in model group was 0. 48 ± 0. 04. Compared with

关 键 词：肺动脉高压 内质网应激 4-苯基丁酸 PERK信号通路 

分 类 号：R972.4[医药卫生—药品]