雌激素对野百合碱诱导的肺动脉高压大鼠右心室重构的影响及其机制。

Effect of estrogen on right ventricular remodeling of monocrotaline-induced pulmonary arterial hypertension in rats and its mechanism.

机构信息

Department of Cardiac Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.

出版信息

Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1742-1750. doi: 10.26355/eurrev_201902_17136.

DOI:10.26355/eurrev_201902_17136

PMID:30840299

Abstract

OBJECTIVE

To elucidate the effect of estrogen on right ventricular remodeling of pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) in rats and its underlying mechanism.

MATERIALS AND METHODS

Male Sprague- Dawley (SD) rats were adaptively fed for one week, and then, randomly divided into control group, MCT group, MCT+17-β estradiol (50 mg·kg-1·d-1) group, and MCT+17-β estradiol (100 mg·kg-1·d-1) group, with 8 rats in each group. PAH rat model was constructed by subcutaneous injection of 60 mg·kg-1 MCT for consecutive 4 weeks. The right external jugular vein was intubated to monitor rat RVSP (right ventricular systolic pressure) and mPAP (mean pulmonary arterial pressure). After animal procedures, RV (right ventricle) and LV+S (left ventricle+ventricular septum) of rat were harvested and weighed. Rat tibia was collected and recorded for its length, followed by calculation of RV/(LV+S) and RV/length of the tibia. HE staining and Masson staining were conducted to observe the pathological change and collagen deposition in RV, respectively. RV was prepared for homogenate, followed by detection of total antioxidant capacity (T-AOC) and malondialdehyde (MDA) activities. Expression levels of collagen I, collagen III, NOX4, and NF-κB in RV of PAH rats were detected by qRT-PCR and Western blot.

RESULTS

Lower RVSP, mPAP, RV/(LV+S) and RV/length of the tibia were observed in rats of MCT+17-β estradiol (50 mg·kg-1·d-1) group and MCT+17-β estradiol (100 mg·kg-1·d-1) group compared with those of MCT group. Injection of 17-β estradiol (50 mg·kg-1·d-1 and 100 mg·kg-1·d-1) in PAH rats remarkably alleviated pathological changes and collagen deposition in RV. T-AOC activity increased, whereas MDA activity decreased in PAH rats injected with 17-β estradiol. Expression levels of collagen I, collagen III, NOX4, and NF-κB in RV of PAH rats were all downregulated by 17-β estradiol treatment.

CONCLUSIONS

17-β estradiol could remarkably alleviate MCT-induced right ventricular remodeling of PAH rats. It is suggested that 17-β estradiol exerts its protective role in PAH by inhibiting NOX4-mediated oxidative stress and NF-κB-mediated collagen deposition.

摘要

目的

阐明雌激素对野百合碱（MCT）诱导的肺动脉高压（PAH）大鼠右心室重构的影响及其作用机制。

材料和方法

雄性 Sprague-Dawley（SD）大鼠适应性喂养一周后，随机分为对照组、MCT 组、MCT+17-β 雌二醇（50 mg·kg-1·d-1）组和 MCT+17-β 雌二醇（100 mg·kg-1·d-1）组，每组 8 只。通过连续 4 周皮下注射 60 mg·kg-1 MCT 构建 PAH 大鼠模型。通过右颈外静脉插管监测大鼠 RVSP（右心室收缩压）和 mPAP（平均肺动脉压）。动物实验后，取大鼠 RV（右心室）和 LV+S（左心室+室间隔）称重。采集大鼠胫骨，记录其长度，计算 RV/（LV+S）和 RV/胫骨长度。分别进行 HE 染色和 Masson 染色观察 RV 病理改变和胶原沉积。制备 RV 匀浆，检测总抗氧化能力（T-AOC）和丙二醛（MDA）活性。采用 qRT-PCR 和 Western blot 检测 RV 中胶原 I、胶原 III、NOX4 和 NF-κB 的表达水平。

结果

与 MCT 组相比，MCT+17-β 雌二醇（50 mg·kg-1·d-1）组和 MCT+17-β 雌二醇（100 mg·kg-1·d-1）组大鼠的 RVSP、mPAP、RV/（LV+S）和 RV/胫骨长度均降低。PAH 大鼠注射 17-β 雌二醇（50 mg·kg-1·d-1 和 100 mg·kg-1·d-1）可显著减轻 RV 病理改变和胶原沉积。PAH 大鼠注射 17-β 雌二醇后 T-AOC 活性增加，MDA 活性降低。17-β 雌二醇处理可下调 PAH 大鼠 RV 中胶原 I、胶原 III、NOX4 和 NF-κB 的表达水平。