2. Academic Validation
  3. Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling

Elabela blunts doxorubicin-induced oxidative stress and ferroptosis in rat aortic adventitial fibroblasts by activating the KLF15/GPX4 signaling

  • Cell Stress Chaperones. 2022 Dec 13. doi: 10.1007/s12192-022-01317-6.
Mi-Wen Zhang 1 2 3,  Xue-Ting Li 1 2 3,  Zhen-Zhou Zhang 1 3,  Ying Liu 1 3,  Jia-Wei Song 1 2 3,  Xin-Ming Liu 1 3,  Yi-Hang Chen 1 3,  Ning Wang 4,  Ying Guo 4,  Li-Rong Liang 5,  Jiu-Chang Zhong 6 7 8
Affiliations

Affiliations

  • 1 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
  • 2 Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
  • 3 Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
  • 4 Department of Geratology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
  • 5 Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. llrcruie@163.com.
  • 6 Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China. jczhong@sina.com.
  • 7 Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. jczhong@sina.com.
  • 8 Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China. jczhong@sina.com.
PMID: 36510036 DOI: 10.1007/s12192-022-01317-6
Abstract

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)-1β, IL6, IL-10, and CXCL1. Intriguingly, knockdown of Krüppel-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.

Keywords

Aortic adventitial fibroblast; Doxorubicin; Elabela; Ferroptosis; Oxidative stress.

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