Prx5 overexpression protect against doxorubicin-induced cardiotoxicity by inhibiting oxidative stress and inflammation via the TLR4/NF-κB pathway

Yewen Hu; Shiqi Wang; Chaoxia Zhang; Caijie Shen; Zhenwei Li; Yongxing Jiang; Jiating Dai; Xiaomin Chen

doi:10.1016/j.intimp.2024.113788

Prx5 overexpression protect against doxorubicin-induced cardiotoxicity by inhibiting oxidative stress and inflammation via the TLR4/NF-κB pathway

Int Immunopharmacol. 2024 Dec 19:146:113788. doi: 10.1016/j.intimp.2024.113788. Online ahead of print.

Authors

Yewen Hu¹, Shiqi Wang¹, Chaoxia Zhang¹, Caijie Shen¹, Zhenwei Li¹, Yongxing Jiang¹, Jiating Dai¹, Xiaomin Chen²

Affiliations

¹ Department of Cardiology, The First Affiliated Hospital Of Ningbo University, Ningbo 315000, Zhejiang Province, China; Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo 315000, Zhejiang Province, China.
² Department of Cardiology, The First Affiliated Hospital Of Ningbo University, Ningbo 315000, Zhejiang Province, China; Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Ningbo 315000, Zhejiang Province, China. Electronic address: chxmin@hotmail.com.

PMID: 39706046
DOI: 10.1016/j.intimp.2024.113788

Abstract

Background: The clinical application of Doxorubicin (DOX) is constrained due to its cardiotoxic side effects. Oxidative stress and inflammation are crucial mechanisms driving doxorubicin-induced cardiotoxicity (DIC). Peroxiredoxin 5 (Prx5) is central to these inflammatory responses. However, the specific role of Prx5 in DIC remains unclear. This study aims to investigate the impacts of Prx5 on DIC and the underlying mechanisms.

Methods: A cardiac-specific Prx5-overexpressing mice was used to establish a doxorubicin (DOX)-induced cardiotoxicity (DIC) model. Neonatal mouse cardiomyocytes (NMCMs) were cultured and stimulated with DOX. Prx5 overexpression or knockdown in cardiomyocytes was achieved using a Prx5-overexpressing adenovirus or small interfering RNA (siRNA), respectively. Echocardiography, histopathological assessments, and molecular techniques were employed to examine the effects and mechanisms of Prx5 on DIC.

Results: Prx5 expression is upregulated in cardiac tissues following DOX administration. In DOX-exposed mice, overexpression of Prx5 significantly improved cardiac function and reduced myocardial injury. It inhibited myocardial hypertrophy and fibrosis, and diminished oxidative stress and inflammatory responses. Conversely, Prx5 knockdown in vitro aggravated DOX-induced cardiomyocyte inflammation and oxidative stress. Mechanistically, overexpression of Prx5 also resulted in the downregulation of Toll-like receptor 4 (TLR4) and phosphorylated P65 expression. Moreover, the protective effects of Prx5 were significantly abrogated by a TLR4 agonist.

Conclusion: Prx5 overexpression could protect against DOX-induced cardiac oxidative stress and inflammation. Mechanistically, Prx5 overexpression potentially inhibits the TLR4/NF-κB signaling pathway to improve DOX-induced myocardial injury. These findings strongly suggest that Prx5 could be a potential candidate target for the treatment of DOX-induced myocardial injury.

Keywords: Cardiotoxicity; Doxorubicin; Peroxiredoxin 5.