Exercise Attenuates Doxorubicin-Induced Myocardial Injury by Inhibiting TSHR and Regulating Macrophage Polarization Through MiR-30d-5p/GALNT7

Overview

Journal J Immunol Res

Publisher Wiley

Specialty Allergy & Immunology

Date 2024 Nov 4

PMID 39493373

Authors

Haiyan Wu

Ruoyu Zhou

Hanxin Kong

Jieqiong Yang

Suijuan Liu

Xiaolin Wei

Kunzhi Li

Yunmei Zhang

Affiliations

Soon will be listed here.

Abstract

Doxorubicin (DOX) is an extensively used chemotherapeutic agent that induces cardiotoxicity. Studies have reported that exercise (EXE) can alleviate DOX-induced cardiotoxicity. Therefore, this study aimed to explore the mechanism by which EXE attenuates DOX-induced myocardial injury. In this study, cell and animal models of DOX-induced myocardial injury were constructed. The animal model was subjected to EXE intervention. In this study, in vitro experiments revealed that miR-30d-5p negatively regulated polypeptide N-acetylgalactosaminyltransferase 7 (GALNT7) and that GALNT7 negatively regulated the expression of thyroid stimulating hormone receptor (TSHR). miR-30d-5p downregulated the expression of GALNT7, promoted the expression of TSHR, and promoted macrophage M1 polarization, thus aggravating cardiomyocyte injury. In vivo experiments revealed that EXE intervention significantly downregulated miR-30d-5p and TSHR expression, upregulated GALNT7, reduced inflammation, and promoted M2 macrophage polarization, thereby alleviating DOX-induced myocardial injury. In addition, overexpression of miR-30d-5p or knockdown of GALNT7 weakened the intervention effect of EXE, whereas overexpression of GALNT7 or knockdown of TSHR promoted the effect of EXE. EXE can modulate the miR-30d-5p/GALNT7 axis to inhibit the expression of TSHR, thereby regulating the polarization of macrophages to the M2 phenotype and ultimately alleviating DOX-induced myocardial injury, which provides new targets and strategies for the clinical treatment of myocardial injury.

References

Yang Q, Li J, Kou C, Zhang L, Wang X, Long Y . Presence of TSHR in NK Cells and Action of TSH on NK Cells. Neuroimmunomodulation. 2021; 29(1):77-84. DOI: 10.1159/000516925. View

Bei Y, Lu D, Bar C, Chatterjee S, Costa A, Riedel I . miR-486 attenuates cardiac ischemia/reperfusion injury and mediates the beneficial effect of exercise for myocardial protection. Mol Ther. 2022; 30(4):1675-1691. PMC: 9077322. DOI: 10.1016/j.ymthe.2022.01.031. View

Wang Y, Cui X, Wang Y, Fu Y, Guo X, Long J . Protective effect of miR378* on doxorubicin-induced cardiomyocyte injury via calumenin. J Cell Physiol. 2018; 233(10):6344-6351. PMC: 6055600. DOI: 10.1002/jcp.26615. View

McCall J, Varney M, Rice E, Dziadowicz S, Hall C, Blethen K . Prenatal Cadmium Exposure Alters Proliferation in Mouse CD4 T Cells LncRNA Snhg7. Front Immunol. 2022; 12:720635. PMC: 8786704. DOI: 10.3389/fimmu.2021.720635. View

Zhao L, Qi Y, Xu L, Tao X, Han X, Yin L . MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Redox Biol. 2018; 15:284-296. PMC: 5975069. DOI: 10.1016/j.redox.2017.12.013. View

Cao Q, Wang N, Ren L, Tian J, Yang S, Cheng H . miR-125a-5p post-transcriptionally suppresses GALNT7 to inhibit proliferation and invasion in cervical cancer cells via the EGFR/PI3K/AKT pathway. Cancer Cell Int. 2020; 20:117. PMC: 7147043. DOI: 10.1186/s12935-020-01209-8. View

Han I, Song H, Ryu J . IL-6 produced by prostate epithelial cells stimulated with Trichomonas vaginalis promotes proliferation of prostate cancer cells by inducing M2 polarization of THP-1-derived macrophages. PLoS Negl Trop Dis. 2020; 14(3):e0008126. PMC: 7138318. DOI: 10.1371/journal.pntd.0008126. View

Fang L, Ellims A, Moore X, White D, Taylor A, Chin-Dusting J . Circulating microRNAs as biomarkers for diffuse myocardial fibrosis in patients with hypertrophic cardiomyopathy. J Transl Med. 2015; 13:314. PMC: 4581079. DOI: 10.1186/s12967-015-0672-0. View

Zhenyu L, Ying W, Zhuang T, Yongchao X, Kim J . Exercise-mediated macrophage polarization modulates the targeted therapeutic effect of NAFLD: a review. Phys Act Nutr. 2023; 27(3):10-16. PMC: 10636506. DOI: 10.20463/pan.2023.0023. View

10.

Ma Z . Effect of anthracycline combined with aerobic exercise on the treatment of breast cancer. Pak J Pharm Sci. 2018; 31(3(Special)):1125-1129. View

11.

Maneechote C, Khuanjing T, Ongnok B, Arinno A, Prathumsap N, Chunchai T . Promoting mitochondrial fusion in doxorubicin-induced cardiotoxicity: a novel therapeutic target for cardioprotection. Clin Sci (Lond). 2022; 136(11):841-860. DOI: 10.1042/CS20220074. View

12.

Tavakoli Dargani Z, Singla R, Johnson T, Kukreja R, Singla D . Exosomes derived from embryonic stem cells inhibit doxorubicin and inflammation-induced pyroptosis in muscle cells. Can J Physiol Pharmacol. 2017; 96(3):304-307. DOI: 10.1139/cjpp-2017-0340. View

13.

Wang Y, Wang C, Fu Z, Zhang S, Chen J . miR-30b-5p inhibits proliferation, invasion, and migration of papillary thyroid cancer by targeting GALNT7 via the EGFR/PI3K/AKT pathway. Cancer Cell Int. 2021; 21(1):618. PMC: 8611849. DOI: 10.1186/s12935-021-02323-x. View

14.

Hu C, Zhang X, Song P, Yuan Y, Kong C, Wu H . Meteorin-like protein attenuates doxorubicin-induced cardiotoxicity via activating cAMP/PKA/SIRT1 pathway. Redox Biol. 2020; 37:101747. PMC: 7558217. DOI: 10.1016/j.redox.2020.101747. View

15.

Li X, Liang J, Qin A, Wang T, Liu S, Li W . Protective effect of Di'ao Xinxuekang capsule against doxorubicin-induced chronic cardiotoxicity. J Ethnopharmacol. 2021; 287:114943. DOI: 10.1016/j.jep.2021.114943. View

16.

Fathi R, Nasiri K, Akbari A, Ahmadi-KaniGolzar F, Farajtabar Z . Exercise protects against ethanol-induced damage in rat heart and liver through the inhibition of apoptosis and activation of Nrf2/Keap-1/HO-1 pathway. Life Sci. 2020; 256:117958. DOI: 10.1016/j.lfs.2020.117958. View

17.

Di W, Amdanee N, Zhang W, Zhou Y . Long-term exercise-secreted extracellular vesicles promote browning of white adipocytes by suppressing miR-191a-5p. Life Sci. 2020; 263:118464. DOI: 10.1016/j.lfs.2020.118464. View

18.

Jiao Y, Zhang T, Zhang C, Ji H, Tong X, Xia R . Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit Care. 2021; 25(1):356. PMC: 8507252. DOI: 10.1186/s13054-021-03775-3. View

19.

Babaei H, Razmaraii N, Assadnassab G, Mohajjel Nayebi A, Azarmi Y, Mohammadnejad D . Ultrastructural and Echocardiographic Assessment of Chronic Doxorubicin-Induced Cardiotoxicity in Rats. Arch Razi Inst. 2020; 75(1):55-62. PMC: 8410154. DOI: 10.22092/ari.2019.116862.1177. View

20.

Yang C, Lu M, Chen W, He Z, Hou X, Feng M . Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques. J Exp Med. 2019; 216(5):1182-1198. PMC: 6504213. DOI: 10.1084/jem.20181473. View