柚皮素对低氧性肺动脉高压大鼠右心室重塑的影响

doi:10.11958/20242178

天津医药 ›› 2025, Vol. 53 ›› Issue (2): 129-134.doi: 10.11958/20242178

柚皮素对低氧性肺动脉高压大鼠右心室重塑的影响

吴宾¹(), 杨自更¹, 张婧², 李书红³, 余凤², 王嘉玮⁴, 李彩玲⁴^,^△()

1 新疆军区总医院核医学科（邮编830099）
2 新疆军区总医院营养科（邮编830099）
3 新疆军区总医院门诊部（邮编830099）
4 新疆军区总医院卫勤训练中心（邮编830099）

收稿日期:2024-12-11 修回日期:2025-01-10 出版日期:2025-02-15 发布日期:2025-02-26
通讯作者: ^△ E-mail：xjjqzyycailing@163.com
作者简介:吴宾（1985），男，主治医师，主要从事肺动脉高压的发生发展机制研究。E-mail：xjwubin9210@163.com
基金资助:
新疆维吾尔自治区自然科学基金面上项目(2022D01C644)

Effect of naringenin on right ventricular remodeling induced by hypoxic pulmonary hypertension

WU Bin¹(), YANG Zigeng¹, ZHANG Jing², LI Shuhong³, YU Feng², WANG Jiawei⁴, LI Cailing⁴^,^△()

1 Department of Nuclear Medicine, General Hospital of Xinjiang Military Command, Urumqi 830099, China
2 Department of Nutrition General Hospital of Xinjiang Military Command, Urumqi 830099, China
3 Department of Out-Patient, General Hospital of Xinjiang Military Command, Urumqi 830099, China
4 Health Service Training Center, General Hospital of Xinjiang Military Command, Urumqi 830099, China

Received:2024-12-11 Revised:2025-01-10 Published:2025-02-15 Online:2025-02-26
Contact: ^△ E-mail：xjjqzyycailing@163.com

吴宾, 杨自更, 张婧, 李书红, 余凤, 王嘉玮, 李彩玲. 柚皮素对低氧性肺动脉高压大鼠右心室重塑的影响[J]. 天津医药, 2025, 53(2): 129-134.

WU Bin, YANG Zigeng, ZHANG Jing, LI Shuhong, YU Feng, WANG Jiawei, LI Cailing. Effect of naringenin on right ventricular remodeling induced by hypoxic pulmonary hypertension[J]. Tianjin Medical Journal, 2025, 53(2): 129-134.

摘要/Abstract

摘要：

目的探讨柚皮素（NAR）在低氧性肺动脉高压（HPH）诱导的右心室重塑中的作用及相关机制。方法将SD大鼠随机分为对照（NC）组、NC+NAR组、HPH组、HPH+NAR组，每组15只。后两组采用低压低氧人工舱建立HPH大鼠模型成功后，NC+NAR组和HPH+NAR组给予NAR 100 mg/（kg·d）灌胃，而NC组和HPH组给予同等体积的生理盐水灌胃，每日1次，连续4周。心脏超声检测舒张末期右室游离壁厚度（RVEDWT）和舒张末期右室内径（RVEDD）；心导管检测大鼠右心室收缩压（RVSP）和平均肺动脉压（mPAP）；计算右心室体质量比（RV/BW）和右心室肥厚指数（RVHI）；Masson染色和天狼星染色右心室，计算胶原容积分数（CVF）；TUNEL染色评估右心室心肌细胞凋亡情况；检测右心室心肌组织中丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性；Western blot检测Rho相关激酶（ROCK）蛋白表达。结果与NC组和NC+NAR组相比，HPH组RVEDWT、mPAP、RVSP、RVHI、RV/BW、右心室CVF、右心室心肌细胞凋亡率，右心室心肌组织中MDA含量、ROCK1和ROCK2蛋白表达增加，RVEDD、右心室心肌组织中SOD活性降低（P<0.05）；与HPH组相比，HPH+NAR组RVEDWT、mPAP、RVSP、RVHI、RV/BW、右心室CVF、右心室心肌细胞凋亡率，右心室心肌组织中MDA含量、ROCK1和ROCK2蛋白表达降低，RVEDD、右心室心肌组织中SOD活性增加（P<0.05）。结论 NAR可减轻HPH诱发的右心室重塑，其机制可能与抑制ROCK信号通路并进一步改善右心室心肌凋亡和氧化应激水平有关。

关键词: 低氧, 高血压, 肺性, rho相关激酶类, 细胞凋亡, 氧化性应激, 柚皮素, 心肌纤维化

Abstract:

Objective To investigate the effect of naringenin (NAR) on right ventricular remodeling induced by hypoxic pulmonary hypertension (HPH) and its related mechanism. Methods SD rats were randomly divided into the control group (NC), the NC+NAR group,the HPH group and the HPH+NAR group, with 15 rats in each group. HPH model was established in a low-pressure hypoxic artificial chamber. After the successful construction of the model, rats in the NC+NAR group and the HPH+NAR group were given NAR 100 mg/ (kg·d) gavage once a day for 4 weeks, while rats in the NC group and the HPH group were given the same volume of normal saline once a day for 4 weeks. Right ventricular free wall thickness (RVEDWT) and end-diastolic right ventricular diameter (RVEDD) were measured by echocardiography. Right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were measured by cardiac catheter. Right ventricular mass ratio (RV/BW) and right ventricular hypertrophy index (RVHI) were calculated. Masson and Sirius staining of right ventricle was used to calculate the collagen volume fraction (CVF). TUNEL staining was used to evaluate the apoptosis of right ventricular cardiomyocytes. The contents of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in right ventricular myocardium were detected. The expression of Rho associated kinase (ROCK) protein was detected by Western blot assay. Results Compared with the NC group and the NC+NAR group, mPAP, RVSP, RVEDWT, RV/BW, RVHI, right ventricular CVF, right ventricular myocardial cell apoptosis rate, MDA content and ROCK1 and ROCK2 protein expression in right ventricular myocardial tissue were increased in the HPH group. RVEDD and SOD activity in right ventricular myocardium were decreased (P<0.05). Compared with the HPH group, mPAP, RVSP, RVEDWT, RV/BW, RVHI, right ventricular CVF, right ventricular myocardial cell apoptosis rate, MDA content, ROCK1 and ROCK2 protein expression in right ventricular myocardial tissue were decreased in the HPH+NAR group, and RVEDD and SOD activity in right ventricular myocardium were increased (P<0.05). Conclusion NAR can reduce HPH-induced right ventricular remodeling, and its mechanism may be related to inhibiting ROCK signaling pathway and further improving apoptosis and oxidative stress in right ventricular myocardium.

Key words: hypoxia, hypertension, pulmonary, rho-associated kinases, apoptosis, oxidative stress, Naringenin, myocardial fibrosis

中图分类号:

R544，R541.3

图/表 9

表1 各组大鼠心功能RVEDD和RVEDWT的比较（n=15，mm，$\bar{x}±s$）

Tab.1 Comparison of RVEDD and RVEDWT in cardiac function between the four groups of rats

组别	RVEDD	RVEDWT
NC组	2.63±0.11	0.38±0.06
NC+NAR组	2.57±0.18	0.37±0.08
HPH组	1.34±0.14^ab	0.93±0.08^ab
HPH+NAR组	2.02±0.19^c	0.66±0.09^c
F	251.400^＊＊	173.800^＊＊

表2 各组mPAP和RVSP水平比较（n=15，mmHg，$\bar{x}±s$）

Tab.2 Comparison of mPAP and RVSP levels between the four groups of rats

组别	mPAP	RVSP
NC组	19.33±2.52	24.84±2.60
NC+NAR组	21.01±2.65	25.83±4.19
HPH组	41.03±4.02^ab	48.21±2.67^ab
HPH+NAR组	30.67±3.51^c	34.60±2.99^c
F	143.800^＊＊	180.800^＊＊

表3 各组RVHI和RV/BW比较（n=15，$\bar{x}±s$）

Tab.3 Comparison of RVHI and RV/BW levels between the four groups of rats

组别	RVHI	RV/BW/（g/kg）
NC组	0.31±0.01	0.70±0.03
NC+NAR组	0.30±0.02	0.68±0.04
HPH组	0.41±0.02^ab	0.94±0.05^ab
HPH+NAR组	0.37±0.02^c	0.81±0.02^c
F	124.200^＊＊	158.800^＊＊

图1 Masson染色检测各组大鼠右心室心肌胶原沉积情况（×400）

Fig.1 Masson staining showing collagen deposition of right ventricle in each group (×400)

图2 天狼星染色检测各组大鼠右心室心肌Ⅰ型胶原沉积情况（×400）

Fig.2 Sirius staining showing collagenⅠdeposition of right ventricle in each group (×400)

图3 各组大鼠右心室心肌凋亡的比较（TUNEL染色，×1 000）绿色：TUNEL；蓝色：DAPI；红色：Troponin T。

Fig.3 Comparison of apoptotic rate of right ventricular cardiomyocytes between the four groups of rats (TUNEL staining, ×1 000)

表4 各组大鼠右心室MDA和SOD水平的比较（n=6，$\bar{x}±s$）

Tab.4 Comparison of MDA and SOD levels in right ventricle between the four groups of rats

组别	MDA/（U/mg）	SOD/（U/mL）
NC组	9.53±1.56	27.90±2.08
NC+NAR组	10.11±1.92	31.19±1.93
HPH组	30.07±2.80^ab	7.07±2.18^ab
HPH+NAR组	21.37±3.09^c	19.03±3.06^c
F	98.970^＊＊	102.200^＊＊

图4 Western blot检测各组大鼠右心室ROCK1和ROCK2蛋白表达水平 A：NC组；B：NC+NAR组；C：HPH组；D：HPH+NAR组。

Fig.4 Western blot assay showing levels of ROCK1 and ROCK2 in right ventricles of rats in each group

表5 各组大鼠右心室ROCK1和ROCK2表达水平比较（n=6，$\bar{x}±s$）

Tab.5 Comparison of ROCK1 and ROCK2 levels in right ventricles between the four groups

组别	ROCK1	ROCK2
NC组	0.35±0.07	0.16±0.02
NC+NAR组	0.39±0.06	0.18±0.03
HPH组	0.98±0.09^ab	0.68±0.07^ab
HPH+NAR组	0.66±0.08^c	0.43±0.06^c
F	89.290^＊＊	143.000^＊＊

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柚皮素对低氧性肺动脉高压大鼠右心室重塑的影响

Effect of naringenin on right ventricular remodeling induced by hypoxic pulmonary hypertension

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