SESN2-mediated AKT/GSK-3β/NRF2 Activation to Ameliorate Adriamycin Cardiotoxicity in High Fat Diet-induced Obese Mice

  • Antioxid Redox Signal. 2023 Jun 2. doi: 10.1089/ars.2022.0156.
Ting Gao  1 ,  Jie Wang B  2 ,  Mengjie Xiao  3 ,  Jie Wang A  4 ,  Shudong Wang  5 ,  Yufeng Tang  6 ,  Jingjing Zhang  7 ,  Guangping Lu  8 ,  Hua Guo  9 ,  Yuanfang Guo  10 ,  Qingbo Liu  11 ,  Jiahao Li  12 ,  Junlian Gu  13
Affiliations
  • 1. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 2. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 3. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 4. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 5. The First Hospital of Jilin University Department of Cardiology, 629163, Changchun, Jilin, China; [email protected].
  • 6. The First Affiliated Hospital of Shandong First Medical University, 66310, Jinan, Shandong, China; [email protected].
  • 7. The First Hospital of China Medical University, 159407, Shenyang, Liaoning, China; [email protected].
  • 8. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 9. Shaanxi Provincial People's Hospital, 159431, Xi'an, Shaanxi, China; [email protected].
  • 10. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 11. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 12. Shandong University Cheeloo College of Medicine, 66555, Jinan, Shandong, China; [email protected].
  • 13. Shandong University Cheeloo College of Medicine, 66555, School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong, 250012, China., Jinan, China, 250012; [email protected].
PMID: 37265150 DOI: 10.1089/ars.2022.0156
Abstract

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high fat diet (HFD)-induced obese mice.

Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity which probably associated with inhibiting Akt, GSK-3β phosphorylation and subsequently blocking nuclear localization of NRF2, ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac damaged effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin, respectively. And sulforaphane (SFN), an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice.

Innovation and conclusion: The present study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by up-regulating activity of NRF2 via Akt/GSK-3β/Fyn signaling pathway.

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