1. Academic Validation
  2. Cardiac SIRT1 ameliorates doxorubicin-induced cardiotoxicity by targeting sestrin 2

Cardiac SIRT1 ameliorates doxorubicin-induced cardiotoxicity by targeting sestrin 2

  • Redox Biol. 2022 Jun;52:102310. doi: 10.1016/j.redox.2022.102310.
Jie Wang A 1 Yufeng Tang 2 Jingjing Zhang 3 Jie Wang B 1 Mengjie Xiao 1 Guangping Lu 1 Jiahao Li 1 Qingbo Liu 1 Yuanfang Guo 1 Junlian Gu 4
Affiliations

Affiliations

  • 1 School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China.
  • 3 Department of Cardiology, The First Hospital of China Medical University, Shenyang, Liaoning, 110016, China; Department of Cardiology, The People's Hospital of Liaoning Province, Shenyang, Liaoning, 110016, China.
  • 4 School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address: junlian_gu@sdu.edu.cn.
Abstract

Although it is known that the expression and activity of Sirtuin 1 (SIRT1) significantly decrease in doxorubicin (DOX)-induced cardiomyopathy, the role of interaction between SIRT1 and sestrin 2 (SESN2) is largely unknown. In this study, we investigated whether SESN2 could be a crucial target of SIRT1 and the effect of their regulatory interaction and mechanism on DOX-induced cardiac injury. Here, using DOX-treated cardiomyocytes and cardiac-specific SIRT1 knockout mice models, we found SIRT1 deficiency aggravated DOX-induced cardiac structural abnormalities and dysfunction, whereas the activation of SIRT1 by resveratrol (RES) treatment or SIRT1 overexpression possessed cardiac protective effects. Further studies indicated that SIRT1 exerted these beneficial effects by markedly attenuating DOX-induced oxidative damage and Apoptosis in a SESN2-dependent manner. Knockdown of Sesn2 impaired RES/SIRT1-mediated protective effects, while upregulation of SESN2 efficiently rescued DOX-induced oxidative damage and Apoptosis. Most importantly, SIRT1 activation could reduce DOX-induced SESN2 ubiquitination possibly through reducing the interaction of SESN2 with mouse double minute 2 (MDM2). The recovery of SESN2 stability in DOX-impaired primary cardiomyocytes by SIRT1 was confirmed by Mdm2-siRNA transfection. Taken together, our findings indicate that disrupting the interaction between SESN2 and MDM2 by SIRT1 to reduce the ubiquitination of SESN2 is a novel regulatory mechanism for protecting hearts from DOX-induced cardiotoxicity and suggest that the activation of SIRT1-SESN2 axis has potential as a therapeutic approach to prevent DOX-induced cardiotoxicity.

Keywords

Apoptosis; Cardiotoxicity; Doxorubicin; Oxidative stress; SESN2; SIRT1.

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