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Updated: Jun 4, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
eEF2K alleviates doxorubicin-induced cardiotoxicity by inhibiting GSK3β and improving autophagy dysfunction
Junjie Guan1,2,3, Hongwei Mo1,2,3, Vicheth Virak1,2,3
1Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, No 253, Middle Gongye Avenue, 510282, Guangzhou, Guangdong, People's Republic of China.
Abstract:
Doxorubicin-induced cardiotoxicity (DIC) poses a threat to the health and prognosis of cancer patients. It is important to find a safe and effective method for the prevention and treatment of DIC. eEF2K, which is a highly conserved α-kinase, is thought to be a therapeutic target for several human diseases. Nonetheless, it is still uncertain if eEF2K contributes to the cardiotoxic effects caused by doxorubicin (DOX). Our research revealed that eEF2K expression decreased in the DIC. eEF2K was overexpressed through adeno-associated virus in vivo and adenovirus in vitro, which presented alleviative cardiomyocyte death and cell atrophy induced by DOX. Autophagy dysfunction is one of important mechanisms in DIC. As a result, autophagic function was evaluated using Transmission electron microscopy in vivo, as well as LysoSensor and mRFPGFP-LC3 puncta in vitro. eEF2K overexpression improves DOX-induced autophagy blockade. In addition, eEF2K knockdown aggravated autophagy blockade and cardiomyocyte injury in DIC model. eEF2K also phosphorylated and inhibited GSK3β in DIC model. AR-A014418 (ARi), known for selectively inhibiting GSK3β, countered the effects of eEF2K knockdown, which aggravated autophagy blockade in the DIC. In conclusion, this study proposes that eEF2K alleviates DIC by inhibiting GSK3β and improving autophagy dysfunction. eEF2K is a promising therapeutic target against DIC.
Insights
eEF2K protects against doxorubicin-induced cardiotoxicity by improving autophagy and inhibiting GSK3β. This discovery highlights eEF2K as a potential therapeutic target for preventing heart damage in cancer patients.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Doxorubicin-induced cardiotoxicity (DIC) is a significant clinical challenge impacting cancer patient outcomes.
- The role of eukaryotic elongation factor 2 kinase (eEF2K) in DIC pathogenesis remains unclear.
- Autophagy dysfunction is implicated as a key mechanism in DIC.
Purpose of the Study:
- To investigate the role of eEF2K in doxorubicin-induced cardiotoxicity.
- To explore the potential of eEF2K as a therapeutic target for DIC.
- To elucidate the molecular mechanisms underlying eEF2K's effects on cardiotoxicity.
Main Methods:
- In vivo and in vitro models of DIC were established.
- eEF2K expression was modulated using viral vectors (AAV and adenovirus).
- Cardiomyocyte viability, autophagy flux (TEM, LysoSensor, mRFPGFP-LC3), and GSK3β phosphorylation were assessed.
Main Results:
- eEF2K expression was reduced in DIC models.
- Overexpression of eEF2K alleviated DOX-induced cardiomyocyte death and atrophy.
- eEF2K overexpression improved DOX-impaired autophagy and inhibited GSK3β.
- Knockdown of eEF2K exacerbated autophagy blockade and cardiac injury.
Conclusions:
- eEF2K plays a protective role against DIC.
- eEF2K alleviates DIC by inhibiting GSK3β and enhancing autophagy.
- eEF2K represents a promising therapeutic target for managing doxorubicin-induced cardiotoxicity.
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