Journal
CELL STRESS & CHAPERONES
Volume 28, Issue 1, Pages 91-103Publisher
SPRINGER
DOI: 10.1007/s12192-022-01317-6
Keywords
Doxorubicin; Elabela; Oxidative stress; Ferroptosis; Aortic adventitial fibroblast
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This study investigated the role of Elabela (ELA) in doxorubicin (DOX)-induced oxidative stress and ferroptosis. The findings revealed that ELA exerted anti-oxidative and anti-ferroptotic effects in rat aortic adventitial fibroblasts (AFs) by activating the KLF15/GPX4 signaling, thereby preventing DOX-induced cytotoxicity.
Doxorubicin (DOX) is a chemotherapeutic drug for a variety of malignancies, while its application is restricted by the cardiovascular toxic effects characterized by oxidative stress. Ferroptosis is a novel iron-dependent regulated cell death driven by lipid peroxidation. Our study aimed to investigate the role of Elabela (ELA) in DOX-induced oxidative stress and ferroptosis. In cultured rat aortic adventitial fibroblasts (AFs), stimulation with DOX dramatically induced cytotoxicity with reduced cell viability and migration ability, and enhanced lactate dehydrogenase (LDH) activity. Importantly, ELA and ferrostatin-1 (Fer-1) mitigated DOX-mediated augmentation of reactive oxygen species (ROS) in rat aortic AFs, accompanied by upregulated levels of Nrf2, SLC7A11, GPX4, and GSH. In addition, ELA reversed DOX-induced dysregulation of apoptosis- and inflammation-related factors including Bax, Bcl2, interleukin (IL)-1 beta, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Kruppel-like factor 15 (KLF15) by siRNA abolished ELA-mediated alleviation of ROS production and inflammatory responses. More importanly, KLF15 siRNA impeded the beneficial roles of ELA in DOX-pretreated rat aortic AFs by suppressing the Nrf2/SLC7A11/GPX4 signaling. In conclusion, ELA prevents DOX-triggered promotion of cytotoxicity, and exerts anti-oxidative and anti-ferroptotic effects in rat aortic AFs via activation of the KLF15/GPX4 signaling, indicating a promising therapeutic value of ELA in antagonizing DOX-mediated cardiovascular abnormality and disorders.
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