Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity

Bin Leng; Lin Deng; Jianxin Tan; Wei-Thye Lee; Cheng-Rui Cao; Zi-Ping Wang; De-Jian Huang; Xiaowei Nie; Jin-Song Bian

doi:10.1016/j.freeradbiomed.2023.04.008

Targeting the Na⁺/K⁺ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity

Free Radic Biol Med. 2023 Aug 1:204:38-53. doi: 10.1016/j.freeradbiomed.2023.04.008. Epub 2023 Apr 24.

Authors

Bin Leng¹, Lin Deng², Jianxin Tan³, Wei-Thye Lee⁴, Cheng-Rui Cao², Zi-Ping Wang², De-Jian Huang⁵, Xiaowei Nie⁶, Jin-Song Bian⁷

Affiliations

¹ Department of Food Science and Technology, National University of Singapore, 2 Science Drive 2, Singapore, 117542, Singapore; National University of Singapore (Suzhou) Research Institute, 377 Linquan Street, Suzhou, 215123, Jiangsu, China.
² Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
³ Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, China.
⁴ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
⁵ Department of Food Science and Technology, National University of Singapore, 2 Science Drive 2, Singapore, 117542, Singapore; National University of Singapore (Suzhou) Research Institute, 377 Linquan Street, Suzhou, 215123, Jiangsu, China. Electronic address: [email protected].
⁶ Shenzhen Key Laboratory of Respiratory Diseases, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518055, China. Electronic address: [email protected].
⁷ Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China; National University of Singapore (Suzhou) Research Institute, 377 Linquan Street, Suzhou, 215123, Jiangsu, China. Electronic address: [email protected].

PMID: 37100355
DOI: 10.1016/j.freeradbiomed.2023.04.008

Abstract

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

Keywords: Cardiotoxicity; Doxorubicin; Ferroptosis; NKAα1; Na(+)/K(+) ATPase; SLC7A11.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / metabolism
Animals
Antibodies / metabolism
Apoptosis
Cardiotoxicity* / drug therapy
Cardiotoxicity* / etiology
Doxorubicin / pharmacology
Heart Diseases* / pathology
Mice
Myocytes, Cardiac / metabolism
Oxidative Stress

Substances

Adenosine Triphosphatases
Doxorubicin
Antibodies