有氧运动对高脂膳食小鼠心肌损伤中Nrf2/GPX4/Ferroptosis通路的作用*

doi:10.12047/j.cjap.6234.2022.026

中国应用生理学杂志 ›› 2022, Vol. 38 ›› Issue (2): 143-148.doi: 10.12047/j.cjap.6234.2022.026

有氧运动对高脂膳食小鼠心肌损伤中Nrf2/GPX4/Ferroptosis通路的作用^*

王海涛^1,2, 杨雯茜³, 刘玉倩^1,2△

1.岭南师范学院运动与健康研究所, 广东湛江 524048;
2.岭南师范学院体育科学学院, 广东湛江 524048;
3.华南师范大学体育科学学院, 广东广州 510631

收稿日期:2021-12-10 修回日期:2022-03-18 出版日期:2022-03-28 发布日期:2022-08-29
通讯作者: ^△Tel: 13171576182; E-mail: liuyq@lingnan.edu.cn
基金资助:
^*岭南师范学院人才专项(ZL2008,ZL2009)

Effects of aerobic exercise on Nrf2/GPX4/Ferroptosis pathway in myocardial injury in high-fat diet mice

WANG Hai-tao^1,2, YANG Wen-qian³, LIU Yu-qian^1,2△

1. Institute of Sports and Health Promotion, Lingnan Normal University, Zhanjiang 524048;
2. School of Physical Education and Sports Science,Lingnan Normal University, Zhanjiang 524048;
3. School of Physical Education and Sports Science, South China Normal University, Guangzhou 510631, China

Received:2021-12-10 Revised:2022-03-18 Online:2022-03-28 Published:2022-08-29

摘要/Abstract

摘要： 目的: 探讨核因子E2相关因子2(Nrf 2)激活谷胱甘肽过氧化物酶4(GPX4)抑制铁死亡(Ferroptosis)的通路在有氧运动预防高脂膳食小鼠心肌损伤中的保护作用。方法: 40只5周龄SPF 级C57BL/6雄性小鼠随机分为安静对照组(NC)、运动组(NE)、高脂组(HC)和高脂+运动组(HE,高脂与跑台运动同时开始),每组10只。高脂膳食采用60% Kcal SPF级高脂模型饲料喂养,自由进食。有氧运动采用递增负荷跑台运动,每周5 d,60 min/d,速度从13 m/min开始,每两周速度递增1 m/min。14周后取心肌和血液。HE染色观察心肌组织结构变化。Western blot 检测心肌Nrf2/GPX4/ Ferroptosis相关蛋白表达。分光光度法测定心肌过氧化物浓度和抗氧化酶活性。ELISA法检测心肌线粒体8-OHdG和血清胰岛素水平。结果: 与对照组相比,高脂组的心肌纤维间隙脂质集聚增加,FBG和FINS显著增加,而ISI显著下降(P＜0.01);与高脂组相比,高脂运动组的心肌纤维间隙脂质集聚减少, T-AOC、T-SOD、GSH活性显著增强,心肌线粒体8-OHdG和心肌铁含量降低(P＜0.01),FPN1、FTH1、GPX4、GLUT1和细胞核内Nrf2显著升高(P＜0.01)。结论: 有氧运动可促进小鼠心肌Nrf2转位入核增强GPX4表达,抑制心肌Ferroptosis发生,同时促进心肌抗氧化酶活性,抑制心肌线粒体过氧化损伤。

关键词: 谷胱甘肽过氧化物酶4, 有氧运动, 铁死亡, 心肌, 小鼠

Abstract: Objective: To illuminate the protective effects of pathway in inhibiting ferroptosis by glutathione peroxidase 4 (GPX4) activated by nuclear factor erythroid 2-related factor 2 (Nrf2) during aerobic exercise against myocardial injury in high-fat diet mice. Methods: Forty 5-week-old SPF C57BL/6 male mice were randomly divided into the control group (NC), the exercise group (NE), the high fat group (HC) and the high fat diet with exercise group (HE, began at the same time). There were 10 mice in each group. The mice in the high fat diet group were fed with 60% Kcal SPF high fat model diet. Aerobic exercise was performed using increasing load platform exercise, 5 days /week, 60 min/d, the speed started from 13m/min, and increased by 1m/min every two weeks. Myocardium and blood samples were collected after 14 weeks. Structural changes of myocardial tissues were observed by HE staining. Western blot was used to detect the expressions of Nrf2/GPX4/Ferroptosis related proteins in myocardium. Myocardial peroxide concentration and antioxidant enzyme activity were measured by spectrophotometry. Myocardial mitochondrial 8-hydroxy-2 deoxyguanosine (8-OHdG) and serum insulin were measured by ELISA. Results: Compared with the NC group, there was more lipid accumulation in the myocardial fiber space in the HC group, and the levels of FBG and FINS were increased significantly, while ISI was decreased significantly (P＜0.01). Compared with the HC group, the lipid concentration was decreased in the HE group, and the activities of total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) and glutathione (GSH) were increased significantly, while the levels of mitochondrial 8-OHdG and myocardial iron content were decreased (P＜0.01). The expression levels of Ferroportin1 (FPN1), ferritin heavy chain 1 (FTH1), GPX4, glucose transporter (GLUT1) and Nrf2 in the HE group were significantly higher than those in the HC group (P＜0.01). Conclusion: The expression of GPX4 was enhanced by more Nrf2 transposition into the nuclear during aerobic exercise, which inhibited the occurrence of myocardial ferroptosis. The activities of antioxidant enzymes were promoted and inhibited the peroxidation damage of myocardial mitochondria.

Key words: glutathione peroxidase 4(GPX 4), aerobic exercise, Ferroptosis, myocardium, mouse

中图分类号:

G804.5

王海涛, 杨雯茜, 刘玉倩. 有氧运动对高脂膳食小鼠心肌损伤中Nrf2/GPX4/Ferroptosis通路的作用^*[J]. 中国应用生理学杂志, 2022, 38(2): 143-148.

WANG Hai-tao, YANG Wen-qian, LIU Yu-qian. Effects of aerobic exercise on Nrf2/GPX4/Ferroptosis pathway in myocardial injury in high-fat diet mice[J]. CJAP, 2022, 38(2): 143-148.

参考文献

[1] Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease [J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282.
[2] Fang X, Wang H, Han D, et al. Ferroptosis as a target for protection against cardiomyopathy[J]. Proc Natl Acad Sci U S A, 2019, 116(7): 2672-2680.
[3] Sumneang N, Siri-Angkul N, Kumfu S, et al. The effects of iron overload on mitochondrial function, mitochondrial dynamics, and ferroptosis in cardiomyocytes [J]. Arch Biochem Biophys, 2020, 680(2): 108241-108255.
[4] Wang F, Min J. DHODH tangoing with GPX4 on the ferroptotic stage[J]. Signal Transduct Target Ther, 2021, 6(1): 244-245.
[5] Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer [J]. Nature, 2021, 593(7860): 586-590.
[6] Kerins MJ, Ooi A. The roles of NRF2 in modulating cellular iron homeostasis[J]. Antioxid Redox Signal, 2018, 29(17): 1756-1773.
[7] 刘玉倩, 张静, 高丽娜, 等. 有氧运动对高糖高脂膳食大鼠腓肠肌Nrf2-SOD的影响[J]. 中国应用生理学杂志, 2020, 36(5): 481-485.
[8] Nichols S, McGregor G, Breckon J, et al. Current insights into exercise-based cardiac rehabilitation in patients with coronary heart disease and chronic heart failure[J]. Int J Sports Med, 2021, 42(1): 19-26.
[9] Ng ACT, Delgado V, Borlaug BA, et al. Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging[J]. Nat Rev Cardiol, 2021, 18(4): 291-304.
[10] Yang W, Liu Y, Yang G, et al. Moderate-intensity physical exercise affects the exercise performance and gut microbiota of mice [J]. Front Cell Infect Microbiol, 2021, 11(9): 917-932.
[11] 徐凡, 张艳美. 不同组织匀浆法对心肌组织线粒体提取质量的影响[J]. 汕头大学医学院学报, 2021, 34(02): 100-103.
[12] Dham D, Roy B, Gowda A, et al. 4-Hydroxy-2-nonenal, a lipid peroxidation product, as a biomarker in diabetes and its complications: challenges and opportunities[J]. Free Radic Res, 2021, 55(5): 547-561.
[13] 郭远盘, 史绍蓉, 徐哲, 等. 长期中小强度有氧运动对大鼠左心室肌蛋白质组差异表达的影响[J]. 中国应用生理学杂志, 2021, 37(6): 673-677.
[14] 李洁, 杜乐乐. 不同剂量补铁对低氧训练大鼠力竭运动后骨骼肌线粒体呼吸链酶复合体活性的影响[J]. 中国应用生理学杂志, 2017, 33(1): 75-77.
[15] Ravingerová T, Kindernay L, Barteková M, et al. The molecular mechanisms of iron metabolism and its role in cardiac dysfunction and cardioprotection [J]. Int J Mol Sci, 2020, 21(21): 7889-7912.
[16] Fang X, Cai Z, Wang H, et al. Loss of cardiac ferritin H facilitates cardiomyopathy via Slc7a11-mediated ferroptosis [J]. Circ Res, 2020, 127(4): 486-501.
[17] Jayakumar D, S Narasimhan KK, Periandavan K. Triad role of hepcidin, ferroportin, and Nrf2 in cardiac iron metabolism: From health to disease [J]. J Trace Elem Med Biol, 2022, 69(1): 126882-126897.
[18] Li W, Li W, Leng Y, et al. Ferroptosis is involved in diabetes myocardial ischemia/reperfusion injury through endoplasmic reticulum stress [J]. DNA Cell Biol, 2020, 39(2): 210-225.
[19] Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition [J]. Nature, 2017, 551(7679): 247-250.
[20] Park TJ, Park JH, Lee GS, et al. Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes [J]. Cell Death Dis, 2019, 10(11): 835-849.

有氧运动对高脂膳食小鼠心肌损伤中Nrf2/GPX4/Ferroptosis通路的作用^*

Effects of aerobic exercise on Nrf2/GPX4/Ferroptosis pathway in myocardial injury in high-fat diet mice

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	武南南, 封芮芮, 张宇, 李光, 曹济民, 殷丽天. Synaptotagmin 1基因敲除对小鼠行为的影响^*[J]. 中国应用生理学杂志, 2022, 38(2): 97-101.
[2]	陈均, 高扬, 苏香楠, 于亮. 6周有氧运动对高脂膳食的ApoE敲除小鼠骨骼肌钙调控的影响^*[J]. 中国应用生理学杂志, 2022, 38(2): 137-142.
[3]	李永荣, 谢海彬, 李红, 孙杰. 地塞米松联合缬沙坦对慢性阻塞性肺疾病小鼠保护作用及机制探讨^*[J]. 中国应用生理学杂志, 2022, 38(2): 149-153.
[4]	陈若玺, 郑胜, 郭春燕, 张强. 黄芪多糖对咪喹莫特诱导小鼠银屑病样皮炎的干预作用及其机制^*[J]. 中国应用生理学杂志, 2022, 38(2): 154-159.
[5]	王煜, 王自立, 王志旺, 李喜香, 李济阳. 润肠通便合剂对便秘模型小鼠结肠MUC2、AQP3的影响^*[J]. 中国应用生理学杂志, 2022, 38(2): 159-162.
[6]	郝凯敏, 刘镇, 王浩玉, 祁文秀. PTK2B与Aβ、Tau和LRP-1在APP/PS1小鼠海马组织和血液中的表达随月龄变化的分析^*[J]. 中国应用生理学杂志, 2022, 38(1): 17-24.
[7]	覃超群, 黄斌, 阳芳, 王昌明, 肖影, 莫艳菊, 廖艺, 高枫. GSK3β/eEF2K信号通路对小鼠肺纤维化过程的影响^*[J]. 中国应用生理学杂志, 2022, 38(1): 32-36.
[8]	马媛, 荀敬, 王波涛, 李棣华, 张琦, 王震宇, 吴瑜. 旋覆代赭汤对食管癌细胞干性的影响^*[J]. 中国应用生理学杂志, 2022, 38(1): 62-67.
[9]	李少情, 张青山, 赵婷, 白婷婷, 宣丽颖, 王羽, 赵明. 黄芪注射液对缺血性心肌病大鼠心肌的保护作用^*[J]. 中国应用生理学杂志, 2022, 38(1): 75-78.
[10]	白林林, 王志华, 宁学聪, 巩翠珂, 李爱敏, 段玉玲, 焦雨佼. IL-17A对慢性阻塞性肺疾病的干预作用及其机制^*[J]. 中国应用生理学杂志, 2021, 37(6): 584-588.
[11]	薛峰, 王辉, 许思多, 刘首挺, 龚永生, 范小芳. 左旋卡尼汀对脂多糖诱导小鼠肺微血管内皮细胞自噬和凋亡的影响^*[J]. 中国应用生理学杂志, 2021, 37(6): 589-593.
[12]	李莉, 黄涵柽. 莱菔子乙醇提取物对ApoE^-/-小鼠血脂血糖及肝脂肪变性的影响^*[J]. 中国应用生理学杂志, 2021, 37(6): 622-627.
[13]	胡佳楠, 姜辉, 李美琦, 朱俐, 骆倩倩. 模拟高原低氧环境对小鼠脾脏铁代谢的影响^*[J]. 中国应用生理学杂志, 2021, 37(6): 628-631.
[14]	李萍, 梁琳琅, 王宇, 侯达, 杨昕, 杨博. 二甲双胍和西格列汀对胰岛素抵抗糖尿病前期KKAy小鼠胰岛β细胞功能的影响^*[J]. 中国应用生理学杂志, 2021, 37(6): 644-649.
[15]	袁前发, 何珏, 徐志忠, 林多朵, 朱敬敬, 温春燕, 段海珍, 王文强. 重复经颅磁刺激联合低剂量氟西汀对CUMS抑郁小鼠的影响^*[J]. 中国应用生理学杂志, 2021, 37(6): 650-653.