苹果多酚对野百合碱诱导的肺动脉高压大鼠肺血管重构的作用和机制*

doi:10.12047/j.cjap.5769.2019.045

中国应用生理学杂志 ›› 2019, Vol. 35 ›› Issue (3): 209-214.doi: 10.12047/j.cjap.5769.2019.045

苹果多酚对野百合碱诱导的肺动脉高压大鼠肺血管重构的作用和机制^*

章书豪¹⁺, 邵思铭²⁺, 陈方政¹, 祝静¹, 陈罗薇¹, 王恒³, 项歆惠², 袁琳波^4△

1. 温州医科大学第一临床医学院,
2. 温州医科大学仁济学院,
3. 温州医科大学眼视光学院,
4. 温州医科大学基础医学院生理教研室, 浙江温州 325000

出版日期:2019-05-28 发布日期:2019-06-28
通讯作者: Tel: 13676452396; E-mail: 81132302@qq.com.
⁺:共同第一作者
基金资助:
地方高校国家级大学生创新创业训练计划(201710343005);温州市科技局(Y20170018);浙江省新苗(2018R413049);温州医科大学科研课题(wyx2018101016,wyx2018101103,wyx2018101116)

Effects of apple polyphenols on monocrotaline-induced pulmonary vascular remodeling in rats and its mechanism

ZHANG Shu-hao¹⁺, SHAO Si-ming²⁺, CHEN Fang-zheng¹, ZHU Jing¹, CHEN Luo-wei¹, WANG heng³, XIANG Xin-hui², YUAN Lin-bo^4△

1. School of the First Clinical Medical Sciences, Wenzhou Medical University;
2. Ren ji College of Wenzhou Medical University;
3. College of Optometry, Wenzhou Medical University;
4. Department of Physiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325000, China

Online:2019-05-28 Published:2019-06-28

摘要/Abstract

摘要： 目的:探讨苹果多酚抑制肺动脉高压大鼠肺动脉血管重构的作用及其机制。方法:雄性SD大鼠随机分为对照组(Con),野百合碱(MCT)组,苹果多酚(APP)组,野百合碱+苹果多酚(MCT+APP)组,每组9只。Con组:每天皮下注射1 ml生理盐水;APP组:隔天按20 mg/kg的剂量腹腔注射苹果多酚;MCT组:按60 mg/kg剂量一次性皮下注射MCT;MCT+APP组:一次性皮下注射60 mg/kg剂量MCT,隔天按20 mg/kg剂量腹腔注射APP,所有处理持续3周。建模完成后,检测各组大鼠平均肺动脉压(mPAP),肺血管阻力(PVR),右心室肥厚指数(RVHI),肺动脉血管环外周长比值(WT%),肺小血管管壁面积和管总面积比值(WA%)。检测肺组织中的白细胞介素1(IL-1),白细胞介素6(IL-6),肿瘤坏死因子α(TNF-α),环氧化酶2(COX-2),髓过氧化物酶(MPO) 等炎症通路相关指标,及肺动脉平滑肌细胞内Ca²⁺和内皮细胞eNOS,NO含量。结果:MCT组大鼠与对照组比较,在动物水平的指标mPAP、PVR、RVHI、WA%、WT%和肺动脉组织内IL-1,IL-6,TNF-α,COX-2,MPO表达量以及肺动脉平滑肌细胞内的Ca^{2 +}浓度明显升高(P＜0.05),而内皮细胞中的eNOS,NO含量明显下降( P＜0. 05) ;苹果多酚治疗组与MCT组大鼠相比上述情况得到改善,其中COX-2和Ca²⁺指标明显下降,且具有统计学意义(P＜0. 05)。结论:苹果多酚可通过抑制MCT引起的肺组织内IL-1,IL-6 ,TNF-α,COX-2升高和肺动脉平滑肌细胞内Ca^{2 +}升高以及内皮细胞中eNOS,NO降低,抑制平滑肌细胞增殖,逆转肺血管重构,缓解肺动脉高压。

关键词: 苹果多酚, 肺动脉高压, 野百合碱(MCT), 大鼠, 细胞因子

Abstract: Objective: To investigate the effects of apple polyphenols on pulmonary vascular remodeling in rats with pulmonary arterial hypertension and its mechanism. Methods: Rats were randomly divided into 4 groups:control (Con) group, monocrotaline (MCT) group, apple polyphenol (APP) group,monocrotaline + apple polyphenol (MCT+APP) group. In Con group, rats received a subcutaneous injection of physical saline. In APP group, rats received intraperitoneal injection of 20 mg/kg APP, every other day. In MCT group, rats received a single subcutaneous injection of MCT(60 mg/kg). In MCT+APP group, rats received subcutaneous injection of 60 mg/kg MCT followed by an intraperitoneal injection of 20 mg/kg APP every other day. All the disposal lasted 3 weeks. Then the PAH-relevant indicators, such as mean pulmonary artery pressure(mPAP), pulmonary vascular resistance(PVR), right ventricular hypertrophy index (RVHI) ,wall thickness (WT%) and wall area (WA%) were tested. After that, the inflammatory pathway related indicators, such as interleukin1(IL-1),interleukin1(IL-6), tumor necrosis factor α(TNF-α), cyclooxygenase 2(COX-2) and myeloperoxidase(MPO) in pulmonary tissue and free intracellular Ca²⁺ in pulmonary smooth muscle cell(PASMC), content of eNOS and NO in endothelial cells were determined. Results: Compared with the control group, the levels of mPAP, PVR, RVHI, WA%, WT%, and IL-1, IL-6, TNF-α, COX-2, MPO in tissue and the expression of Ca^{2 +} in PASMC of MCT group were increased significantly, while the contents of eNOS and NO in endothelial cells were decreased significantly (P＜0.05). Compared with the MCT group, the apple polyphenol treatment could improve the above mentioned situation, and the COX-2 and Ca²⁺ indicators of the apple polyphenol treatment group were decreased significantly (P＜0.05). Conclusion: MCT can increase COX-2 expression and intracellular Ca²⁺ in pulmonary artery smooth muscle cells, decrease the contents of eNOS and NO in endothelial cells, while apple polyphenols can significantly inhibit these effects.

Key words: apple polyphenol, pulmonary arterial hypertension, pulmonary arterial smooth muscle cell, rat, COX-2, intracellular Ca²⁺

章书豪, 邵思铭, 陈方政, 祝静, 陈罗薇, 王恒, 项歆惠, 袁琳波. 苹果多酚对野百合碱诱导的肺动脉高压大鼠肺血管重构的作用和机制^*[J]. 中国应用生理学杂志, 2019, 35(3): 209-214.

ZHANG Shu-hao, SHAO Si-ming, CHEN Fang-zheng, ZHU Jing, CHEN Luo-wei, WANG heng, XIANG Xin-hui, YUAN Lin-bo. Effects of apple polyphenols on monocrotaline-induced pulmonary vascular remodeling in rats and its mechanism[J]. CJAP, 2019, 35(3): 209-214.

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苹果多酚对野百合碱诱导的肺动脉高压大鼠肺血管重构的作用和机制^*

Effects of apple polyphenols on monocrotaline-induced pulmonary vascular remodeling in rats and its mechanism

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