Department of Pediatric Cardiovasology, Children's Medical Center, The Second Xiangya Hospital, Central South University, Changsha, China.
Department of Neonatology, Xiangya Hospital, Central South University, Changsha, China.
Cardiovasc Ther. 2023 Feb 22;2023:2108584. doi: 10.1155/2023/2108584. eCollection 2023.
Doxorubicin-induced cardiotoxicity has been closely concerned in clinical practice. Rev-erb is a transcriptional repressor that emerges as a drug target for heart diseases recently. This study is aimed at investigating the role and mechanism of Rev-erb in doxorubicin-induced cardiotoxicity.
H9c2 cells were treated with 1.5 M doxorubicin, and C57BL/6 mice were treated with a 20 mg/kg cumulative dose of doxorubicin to construct doxorubicin-induced cardiotoxicity models in vitro and in vivo. Agonist SR9009 was used to activate Rev-erb. PGC-1 expression level was downregulated by specific siRNA in H9c2 cells. Cell apoptosis, cardiomyocyte morphology, mitochondrial function, oxidative stress, and signaling pathways were measured.
SR9009 alleviated doxorubicin-induced cell apoptosis, morphological disorder, mitochondrial dysfunction, and oxidative stress in H9c2 cells and C57BL/6 mice. Meanwhile, PGC-1 and downstream signaling NRF1, TAFM, and UCP2 expression levels were preserved by SR9009 in doxorubicin-treated cardiomyocytes in vitro and in vivo. When downregulating PGC-1 expression level by specific siRNA, the protective role of SR9009 in doxorubicin-treated cardiomyocytes was attenuated with increased cell apoptosis, mitochondrial dysfunction, and oxidative stress.
Pharmacological activation of Rev-erb by SR9009 could attenuate doxorubicin-induced cardiotoxicity through preservation of mitochondrial function and alleviation of apoptosis and oxidative stress. The mechanism is associated with the activation of PGC-1 signaling pathways, suggesting that PGC-1 signaling is a mechanism for the protective effect of Rev-erb against doxorubicin-induced cardiotoxicity.
多柔比星诱导的心脏毒性在临床实践中受到密切关注。Rev-erb 是一种转录抑制剂，最近成为心脏病的药物靶点。本研究旨在探讨 Rev-erb 在多柔比星诱导的心脏毒性中的作用和机制。
用 1.5 M 多柔比星处理 H9c2 细胞，用 20 mg/kg 累积剂量的多柔比星处理 C57BL/6 小鼠，在体外和体内构建多柔比星诱导的心脏毒性模型。使用激动剂 SR9009 激活 Rev-erb。用特异性 siRNA 下调 H9c2 细胞中 PGC-1 的表达水平。测量细胞凋亡、心肌细胞形态、线粒体功能、氧化应激和信号通路。
SR9009 缓解了多柔比星诱导的 H9c2 细胞和 C57BL/6 小鼠的细胞凋亡、形态紊乱、线粒体功能障碍和氧化应激。同时，SR9009 在体外和体内保存了多柔比星处理的心肌细胞中 PGC-1 和下游信号 NRF1、TAFM 和 UCP2 的表达水平。用特异性 siRNA 下调 PGC-1 的表达水平后，SR9009 在多柔比星处理的心肌细胞中的保护作用减弱，同时伴有细胞凋亡、线粒体功能障碍和氧化应激增加。
SR9009 通过保存线粒体功能和减轻凋亡和氧化应激来抑制多柔比星诱导的心脏毒性。该机制与 PGC-1 信号通路的激活有关，表明 PGC-1 信号通路是 Rev-erb 对多柔比星诱导的心脏毒性的保护作用的机制。
