2. Academic Validation
  3. Elabela ameliorates doxorubicin-induced cardiotoxicity by promoting autophagic flux through TFEB pathway

Elabela ameliorates doxorubicin-induced cardiotoxicity by promoting autophagic flux through TFEB pathway

  • Pharmacol Res. 2022 Apr;178:106186. doi: 10.1016/j.phrs.2022.106186.
Deshu Chen 1,  Wenjie Yu 1,  Chongbin Zhong 1,  Qingqing Hong 1,  Guanlin Huang 1,  Dongdong Que 1,  Yuxi Wang 1,  Yashu Yang 1,  Bowen Rui 1,  Zhenyu Zhuang 1,  Miaoyuan Liang 1,  Zhicheng Ye 1,  Xin Yan 1,  Jiankun Lv 1,  Ronghua Zhang 1,  Jing Yan 2,  Pingzhen Yang 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China.
  • 2 Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China. Electronic address: yanve1008@126.com.
  • 3 Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Guangzhou, Guangdong, China; Heart Center of Zhujiang Hospital, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, Guangdong, China. Electronic address: y_pingzhen@126.com.
PMID: 35306141 DOI: 10.1016/j.phrs.2022.106186
Abstract

Doxorubicin (DOX) is a widely used and effective antineoplastic drug; however, its clinical application is limited by cardiotoxicity. A safe and effective strategy to prevent from doxorubicin-induced cardiotoxicity (DIC) is still beyond reach. Elabela (ELA), a new APJ ligand, has exerted cardioprotective effect against multiple cardiovascular diseases. Here, we asked whether ELA alleviates DIC. Mice were injected with DOX to established acute DIC. In vivo studies were assessed with echocardiography, serum cTnT and CK-MB, HW/BW ratio and WGA staining. Cell death and atrophy were measured by AM/PI staining and phalloidin staining respectively in vitro. Autophagic flux was monitored with Transmission electron microscopy in vivo, as well as LysoSensor and mRFP-GFP-LC3 puncta in vitro. Our results showed that ELA improved cardiac dysfunction in DIC mice. ELA administration also attenuated cell death and atrophy in DOX-challenged neonatal rat cardiomyocytes (NRCs). Additionally, we found that ELA restored DOX-induced autophagic flux blockage, which was evidenced by the reverse of p62 and LC3II, improvement of lysosome function and accelerated degradation of accumulated autolysosomes. Chloroquine, a classical autophagic flux inhibitor, blunted the improvement of ELA on cardiac dysfunction. At last, we revealed that ELA reversed DOX-induced downregulation of transcription factor EB (TFEB), and silencing TFEB by siRNA abrogated the effects of ELA on autophagic flux as well as cell death and atrophy in NRCs. In conclusion, this study indicated that ELA ameliorated DIC through enhancing autophagic flux via activating TFEB. ELA may become a potential target against DIC.

Keywords

Autophagic flux; Cardiotoxicity; Doxorubicin; Elabela; Transcription factor EB.

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