Zhou Shuang, Meng Zhuo, Lu Lin, Xie Junhao, Li Lihua, Cheng Huilong, Sun Kun, Wang Juxiang
Department of Intensive Care Unit, Xiamen Cardiovascular Hospital, Xiamen University, No. 2999, Jinshan Road, Huli District, Xiamen, Fujian, China.
Department of Pediatric Cardiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cardiovasc Toxicol. 2025 May 19. doi: 10.1007/s12012-025-10010-w.
Cardiac fibrosis, oxidative stress, and cardiomyocyte apoptosis are key contributors to the progression of doxorubicin (DOX)-induced cardiotoxicity. ELABELA (ELA) is an early endogenous ligand of apelin receptor (APJ/APLNR), which is a G protein-coupled receptor with seven transmembrane domains. Our present study aimed to investigate the protective role and underlying mechanism of ELA-32 in mitigating oxidative stress and fibrosis associated with DOX-induced cardiotoxicity. Using a mouse model of chronic DOX cardiotoxicity (5 mg/kg, i.p, once a week for four times, the total cumulative dose is 20 mg/kg), it was found that exogenous administration of ELA-32 using a microinjection pump significantly improved cardiac function, reduced oxidative stress, and myocardial fibrosis, and enhanced survival. Furthermore, pretreatment with ELA-32 peptide protected rat cardiomyocytes (H9C2 cells) from DOX-induced cytotoxicity in vitro. However, these cardioprotective effects of ELA-32 were no longer observed after activation of the Smad signaling pathway using TGF-β1. In summary, ELA-32 attenuated DOX-induced cardiac fibrosis through by modulating the TGF-β/Smad signaling pathway, thus highlighting its potential as a therapeutic agent for preventing chronic DOX-related cardiotoxicity.
心脏纤维化、氧化应激和心肌细胞凋亡是阿霉素（DOX）诱导的心脏毒性进展的关键因素。ELABELA（ELA）是apelin受体（APJ/APLNR）的早期内源性配体，APJ/APLNR是一种具有七个跨膜结构域的G蛋白偶联受体。我们目前的研究旨在探讨ELA-32在减轻与DOX诱导的心脏毒性相关的氧化应激和纤维化方面的保护作用及潜在机制。使用慢性DOX心脏毒性小鼠模型（5mg/kg，腹腔注射，每周一次，共四次，总累积剂量为20mg/kg），发现使用微量注射泵外源性给予ELA-32可显著改善心脏功能、降低氧化应激和心肌纤维化，并提高生存率。此外，用ELA-32肽预处理可在体外保护大鼠心肌细胞（H9C2细胞）免受DOX诱导的细胞毒性。然而，使用TGF-β1激活Smad信号通路后，ELA-32的这些心脏保护作用不再出现。总之，ELA-32通过调节TGF-β/Smad信号通路减轻DOX诱导的心脏纤维化，从而突出了其作为预防慢性DOX相关心脏毒性治疗药物的潜力。
