有氧运动通过氧化应激-炎症-Hippo/YAP通路轴改善心力衰竭小鼠心功能

doi:10.12122/j.issn.1673-4254.2026.04.04

摘要/Abstract

摘要：

目的探讨有氧运动通过调控氧化应激、炎症与Hippo-YAP信号通路改善主动脉弓缩窄（TAC）诱导心力衰竭的作用机制。方法 30只C57BL/6J雄性小鼠随机分为假手术组（Sham）、TAC模型组（TAC）及TAC+有氧运动组（TACE），10只/组。TACE组进行4周跑台有氧训练（强度递增）。干预后采用超声心动图评估心功能，Masson染色观察心肌纤维化，ELISA检测血清BNP、炎症因子（TNF-α、IL-6、IL-1β）及氧化应激指标（MDA、SOD、GSH-Px）。RT‑PCR与Western blotting分别检测心肌组织Hippo‑YAP通路相关基因及蛋白表达。通过生物信息学分析各指标相关性。结果与TAC组相比，TACE组心脏质量与心质量指数降低（P<0.01），左心室射血分数（LVEF）、左心室缩短分数（LVFS）及E/A比值升高（P<0.05），心肌纤维化减轻（P<0.05），血清与心肌BNP表达下降（P<0.05）。TACE组血清TNF‑α、IL‑6、IL‑1β及MDA水平降低（P<0.05），SOD与GSH‑Px活性升高（P<0.05）。RT‑PCR结果显示，TACE组心肌Mst1、Lats1、Lats2及YAP1 mRNA表达较TAC组下调（P<0.05）。Western blotting结果显示，TACE组心肌Mst1/2、Lats1/2及YAP总蛋白表达降低，而p‑Lats1/2与p‑YAP水平升高（P<0.05）。相关性分析提示氧化应激、炎症指标与Hippo‑YAP通路表达显著相关。结论有氧运动可改善TAC诱导的心力衰竭小鼠心功能，减轻心肌肥厚与纤维化，其保护作用可能与抑制氧化应激、炎症反应及调控Hippo‑YAP信号通路有关。

关键词: 有氧运动, 心肌肥厚, 氧化应激, Hippo-YAP, 心力衰竭, 心脏功能

Abstract:

Objective To investigate the mechanism by which aerobic exercise improves transverse aortic constriction (TAC)-induced heart failure in mice. Methods Thirty male C57BL/6J mice were randomized into sham-operated group, TAC model group, and TAC with aerobic exercise (TACE) group. The mice in TACE group underwent a 4-week progressive treadmill training starting on day 3 following TAC modeling. Echocardiography and Masson's trichrome staining were used to assess cardiac function and myocardial fibrosis of the mice, respectively, and serum levels of BNP, TNF-α, IL-6, IL-1β, MDA, SOD, and GSH-Px were measured using ELISA. The mRNA and protein expressions of Hippo-YAP pathway components in the myocardial tissue were detected using RT‑PCR and Western blotting, respectively. Bioinformatics analysis was performed to explore the correlations among the measured indicators. Results Compared with those in TAC group, the mice in TACE group showed significantly reduced heart weight and heart weight/body weight ratio, increased left ventricular ejection fraction, left ventricular fractional shortening, and E/A ratio, reduced myocardial fibrosis, decreased BNP expression in both the serum and myocardial tissue, lowered serum levels of TNF‑α, IL‑6, IL‑1β, and MDA, and increased SOD and GSH-Px activities. The mRNA expressions of Mst1, Lats1, Lats2, and YAP1 were significantly downregulated in TACE group as compared with those in TAC group. Western blotting revealed decreased total protein expressions of Mst1/2, Lats1/2, and YAP and increased expression levels of phosphorylated Lats1/2 and phosphorylated YAP in TACE group. Correlation analysis suggested significant associations of oxidative stress markers and inflammatory factors with the expressions of the Hippo-YAP pathway components. Conclusion Aerobic exercise improves cardiac function and attenuates cardiac remodeling in mice with TAC-induced heart failure possibly by suppressing oxidative stress and inflammation and modulating the Hippo-YAP pathway.

Key words: aerobic exercise, cardiac hypertrophy, oxidative stress, Hippo-YAP, heart failure, cardiac function

张国栋, 魏思昂, 王弘, 谢艳丽, 何晖, 李嵘. 有氧运动通过氧化应激-炎症-Hippo/YAP通路轴改善心力衰竭小鼠心功能[J]. 南方医科大学学报, 2026, 46(4): 753-760.

Guodong ZHANG, Siang WEI, Hong WANG, Yanli XIE, Hui HE, Rong LI. Aerobic exercise produces cardioprotective effects in mice by regulating the oxidative stress-inflammation-Hippo/YAP signaling axis[J]. Journal of Southern Medical University, 2026, 46(4): 753-760.

图/表 9

表1 各基因的引物序列

Tab.1 Primer sequences for RT-PCR

Gene name	Forward primer	Reverse primer
BNP	GAGGTCACTCCTATCCTCTGG	GCCATTTCCTCCGACTTTTCTC
Mst1	CTCACCACTGAATGACTTCCAG	AAGGCCCGACAGTCCAGAA
Last1	AAAGCCAGAAGGGTACAGACA	CCTCAGGGATTCTCGGATCTC
Lats2	GGACCCCAGGAATGAGCAG	CCCTCGTAGTTTGCACCACC
YAP1	ACCCTCGTTTTGCCATGAAC	TGTGCTGGGATTGATATTCCGTA
GAPDH	TGGCCTTCCGTGTTCCTAC	GAGTTGCTGTTGAAGTCGCA

图1 有氧运动对TAC 手术小鼠体质量、心脏质量、心脏质量/体质量比的影响

Fig.1 Effects of aerobic exercise on body weight (A), heart weight (B), and HW/BW ratio (C) in mice following transverse aortic constriction (TAC) surgery (Mean±SD, n=10). *P<0.05, **P<0.01, ***P<0.001.

图2 有氧运动对TAC手术小鼠心脏功能的影响

Fig.2 Effects of aerobic exercise on cardiac function in TAC mice (Mean±SD, n=10). A: Echocardiography. B: Ejection fraction (%). C: Fraction shortening (%). D: E/A ratio. *P<0.05, **P<0.01, ***P<0.001.

图3 有氧运动对 TAC 手术小鼠心肌细胞横截面积、纤维化的影响

Fig.3 Effects of aerobic exercise on cross sectional area and fibrosis of cardiomyocytes in TAC mice (Mean±SD, n=10). A: Mass staining of the myocardium in each group (Original magnification: ×200). B: Cross sectional areas of myocardial cells in each group. C: Percentage of cardiac fibrosis (%) in each group. **P<0.01, ***P<0.001.

图4 有氧运动对TAC小鼠BNP变化的结果

Fig.4 Effect of aerobic exercise on BNP changes in TAC mice (Mean±SD, n=10). A: Serum BNP content. B: Relative BNP mRNA expression levels in the heart. *P<0.05, ***P<0.001.

表2 各组小鼠血清 MDA， SOD 和 GSH-Px 的水平

Tab.2 Levels of MDA, SOD, and GSH-Px in serum of the mice in each group (Mean±SD, n=10)

Group	MDA (ng/mL)	SOD (pg/mL)	GSH-Px (μg/mL)
Sham	7.93±0. 54	161.97±11.34	10.72±0.87
TAC	15.35±0.83*	92.68±8.71*	4.27±0.57*
TACE	10.37±0.62*^#	135.41±9.38*^#	9.24±0.92^#

表3 各组小鼠血清 TNF-α， IL-1β 和 IL-6 的表达水平

Tab.3 Serum levels of TNF-α, IL-1β, and IL-6 in the mice in each group (Mean±SD, n=10)

Group	TNF-α (pg/mL)	IL-6 (pg/mL)	IL-1β (pg/mL)
Sham	9.27±0.82	19.37±1.27	79.61±4.89
TAC	36.78±2.34*	68.46±3.09*	164.97±13.28*
TACE	18.69±1.02*^#	35.34±2.56*^#	134.26±9.63*^#

图5 有氧运动对TAC小鼠心肌组织中Hippo-YAP信号通路蛋白表达水平的影响

Fig.5 Effects of aerobic exercise on expression levels of Hippo YAP signaling pathway proteins in the myocardial tissue of TAC mice (Mean±SD, n=10). A: Relative Mst1 mRNA expression levels. B: Relative Lats1 mRNA expression level. C: Relative Lats2 mRNA expression level. D: Relative YAP mRNA expression level. E: Western blotting bands of Mst1/2, Lats1/2, p-Lats1/2, YAP, and p-YAP proteins. F: Quantitative analysis of Mst1/2, Lats1/2, p-Lats1/2, YAP, and p-YAP protein levels. *P<0.05, **P<0.01, ***P<0.001.

图6 各项指标相关性

Fig.6 Correlation of the indicators (Mean±SD, n=10). A: Delivery results of oxidative stress, inflammatory factors, and Hippo YAP signaling pathway in each group of mice. B: Correlation heatmap of various indicators. The intensity of colors in a heatmap indicates the degree of correlation.

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