4-苯基丁酸抑制内质网应激反应改善大鼠肺动脉高压右心衰竭的实验研究

Study of 4-phenylbutyric acid ameliorating right ventricular failure in pulmonary artery hypertension rats by reducing endoplasmic reticulum stress

目的探讨内质网应激(ERS)分子伴侣4-苯基丁酸(4-PBA)对野百合碱(MCT)所致肺动脉高压(PAH)大鼠右心衰竭的影响。方法 32只SD大鼠分为空白对照组(CON组)、空白对照+4-PBA组(CON+PBA组)、MCT模型组(MCT组),MCT+4-PBA治疗组(MCT+PBA组),每组各8只,MCT(60 mg/kg)腹腔注射建立PAH大鼠右心衰竭模型,造模后4-PBA(500 mg/kg)灌胃4周,右心导管测量右心室收缩压(RVSP)和平均肺动脉压(mPAP),计算右心肥厚指数(RVHI),HE染色观察右心形态学变化,ELISA法测定氨基末端B型利钠肽前体(NT-pro BNP)水平,Westen blot检测右心室葡萄糖调节蛋白78(GRP78)及C/EBP环磷酸腺苷反应元件结合转录因子同源蛋白(CHOP)的表达。结果与CON组比较,MCT组大鼠mPAP、RVSP、RVHI、NT-proBNP明显升高,差异有统计学意义(P<0.05),心肌细胞明显肥大,GRP78和CHOP蛋白表达明显增加,差异有统计学意义(P<0.05);与MCT组比较,MCT+PBA组大鼠mPAP、RVSP、RVHI、NT-proBNP明显下降,差异有统计学意义(P<0.05),心肌细胞肥大明显改善,GRP78和CHOP蛋白表达下调,差异有统计学意义(P<0.05)。结论 ERS在PAH、右心衰竭发生过程中发挥重要作用,而4-PBA可以改善右心衰竭,其机制可能与抑制ERS有关。

Objective To investigate the effects of endoplasmic reticulum stress （ERS） molecular chaperone 4-phenyl bu- tyric acid （4-PBA） on right ventricular failure in pulmonary artery hypertension rats induced by monocrotaline （MCT）. Methods 32 SD rats were divided into four groups： black control group （CON group）, black control＋4-PBA group （CON＋PBA group）, MCT model group （MCT group）, MCT＋4-PBA treatment group （MCT＋FBA group）, with eight rats in each group. Right ventricular failure was induced in rats by intraperitoneal injection of MCT （60 mg/kg）, after molding, 4-PBA （500 mg/kg） gavage were given for 4 weeks, mean pulmonary arterial pressure （mPAP） and right ventricular systolic pressure （RVSP） were measured by fight cardiac catheterization, right ventricular hypertrophy index （RVHI） was calculated as the weight ratio of right ventricle to left ventricle plus septum, the fight ventricular histopathological changes were observed by HE, the level of serum N-terminal B type natriuretic peptide （NT-proBNP） was determined by ELISA, and the level of ERS related proteins glucose-regulated protein 78 （GRP78） and C/EBP homologous protein （CHOP） protein expressions in fight ventricle were determined by Westen blot. Results Compared with CON group, the levels of mPAP, RVSP, RVHI and NT-proBNP were obviously increased in MCT group, the differences were statistically significant （P 〈 0.05）, the degree of cardiomyocyte hypertrophy was significantly, and the level of GRP78 and CHOP protein expression were upregulated significantly, the differences were statistically significant （P 〈 0.05）. Compared with MCT group, the level of mPAP, RVSP, RVHI, and NT proBNP in MCT＋PBA group obviously de- creased, the differences were statistically significant （P 〈 0.05）, the degree of cardiomyocyte hypertrophy showed im- proved, and the GRP78 and CHOP protein expression were lower, the differences were statistically significant （P 〈 0.05）. Conclusion ERS plays an important role in the process of right heart failure induced by PAH, and 4 -PBA can improve right heart failure, its mechanism may be related to inhibiting ERS.