2. Academic Validation
  3. SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation

SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation

  • Pharmacol Res. 2021 Jul;169:105642. doi: 10.1016/j.phrs.2021.105642.
Yanping Zhang 1,  Le Ni 2,  Bowen Lin 2,  Lingjie Hu 2,  Zheyi Lin 2,  Jian Yang 2,  Jinyu Wang 3,  Honghui Ma 2,  Yi Liu 2,  Jian Yang 4,  Jianghua Lin 4,  Liang Xu 2,  Liqun Wu 5,  Dan Shi 6
Affiliations

Affiliations

  • 1 Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
  • 3 Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
  • 4 Jinzhou Medical University, Liaoning 121000, China.
  • 5 Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: wuliqun89@hotmail.com.
  • 6 Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: shidan@tongji.edu.cn.
PMID: 33933636 DOI: 10.1016/j.phrs.2021.105642
Abstract

Anthracyclines including doxorubicin (DOX) are still the most widely used and efficacious antitumor drugs, although their cardiotoxicity is a significant cause of heart failure. Despite considerable efforts being made to minimize anthracycline-induced cardiac adverse effects, little progress has been achieved. In this study, we aimed to explore the role and underlying mechanism of SNX17 in DOX-induced cardiotoxicity. We found that SNX17 was downregulated in cardiomyocytes treated with DOX both in vitro and in vivo. DOX treatment combined with SNX17 interference worsened the damage to neonatal rat ventricular myocytes (NRVMs). Furthermore, the rats with SNX17 deficiency manifested increased susceptibility to DOX-induced cardiotoxicity (myocardial damage and fibrosis, impaired contractility and cardiac death). Mechanistic investigation revealed that SNX17 interacted with leiomodin-2 (LMOD2), a key regulator of the thin filament length in muscles, via its C-TERM domain and SNX17 deficiency exacerbated DOX-induced cardiac systolic dysfunction by promoting aberrant LMOD2 degradation through lysosomal pathway. In conclusion, these findings highlight that SNX17 plays a protective role in DOX-induced cardiotoxicity, which provides an attractive target for the prevention and treatment of anthracycline induced cardiotoxicity.

Keywords

Cardiotoxicity; Contractility; Doxorubicin; LMOD2; SNX17.

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