Hu Yewen, Wang Shiqi, Zhang Chaoxia, Shen Caijie, Li Zhenwei, Jiang Yongxing, Dai Jiating, Chen Xiaomin
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.
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.
Int Immunopharmacol. 2025 Jan 27;146:113788. doi: 10.1016/j.intimp.2024.113788. Epub 2024 Dec 19.
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.
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.
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.
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.
阿霉素（DOX）因其心脏毒性副作用，其临床应用受到限制。氧化应激和炎症是导致阿霉素诱导的心脏毒性（DIC）的关键机制。过氧化物酶体增殖物激活受体5（Prx5）在这些炎症反应中起核心作用。然而，Prx5在DIC中的具体作用仍不清楚。本研究旨在探讨Prx5对DIC的影响及其潜在机制。
使用心脏特异性过表达Prx5的小鼠建立阿霉素（DOX）诱导的心脏毒性（DIC）模型。培养新生小鼠心肌细胞（NMCMs）并用DOX刺激。分别使用过表达Prx5的腺病毒或小干扰RNA（siRNA）在心肌细胞中实现Prx5的过表达或敲低。采用超声心动图、组织病理学评估和分子技术来研究Prx5对DIC的影响及机制。
DOX给药后，心脏组织中Prx5表达上调。在DOX暴露的小鼠中，Prx5的过表达显著改善了心脏功能并减少了心肌损伤。它抑制了心肌肥大和纤维化，并减轻了氧化应激和炎症反应。相反，体外敲低Prx5加重了DOX诱导的心肌细胞炎症和氧化应激。机制上，Prx5的过表达还导致Toll样受体4（TLR4）和磷酸化P65表达的下调。此外，TLR4激动剂显著消除了Prx5的保护作用。
Prx5的过表达可以保护免受DOX诱导的心脏氧化应激和炎症。机制上，Prx5的过表达可能抑制TLR4/NF-κB信号通路，以改善DOX诱导的心肌损伤。这些发现强烈表明，Prx5可能是治疗DOX诱导的心肌损伤的潜在候选靶点。
