PARP-2 mediates cardiomyocyte aging and damage induced by doxorubicin through SIRT1 Inhibition

Chaoming Huang; Xuan Zhang; Shulin Wang; Ao Shen; Tianfen Xu; Yanhong Hou; Shuhan Gao; Yongwan Xie; Yi Zeng; Jiayu Chen; Runxiang Lin; Yu Zhang; Chunpeng Wan; Yi Cai

doi:10.1007/s10495-023-01929-y

PARP-2 mediates cardiomyocyte aging and damage induced by doxorubicin through SIRT1 Inhibition

Apoptosis. 2024 Jan 28. doi: 10.1007/s10495-023-01929-y. Online ahead of print.

Authors

Chaoming Huang^#¹, Xuan Zhang^#¹, Shulin Wang², Ao Shen¹, Tianfen Xu³, Yanhong Hou¹, Shuhan Gao¹, Yongwan Xie⁴, Yi Zeng¹, Jiayu Chen¹, Runxiang Lin¹, Yu Zhang⁵, Chunpeng Wan⁶, Yi Cai⁷

Affiliations

¹ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
² Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511500, Qingyuan, China.
³ Department of Medical Genetics and Cell Biology, GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
⁴ School of Public Health, Guangzhou Medical University, Guangzhou, 511436, China.
⁵ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. qianedyzy@gzhmu.edu.cn.
⁶ Research Center of Tea and Tea Culture, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, China. chunpengwan@jxau.edu.cn.
⁷ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China. yicaisysu@163.com.

^# Contributed equally.

PMID: 38281279
DOI: 10.1007/s10495-023-01929-y

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic used as an antitumor treatment. However, its clinical application is limited due to severe side effects such as cardiotoxicity. In recent years, numerous studies have demonstrated that cellular aging has become a therapeutic target for DOX-induced cardiomyopathy. However, the underlying mechanism and specific molecular targets of DOX-induced cardiomyocyte aging remain unclear. Poly (ADP-ribose) polymerase (PARP) is a family of protein post-translational modification enzymes in eukaryotic cells, including 18 members. PARP-1, the most well-studied member of this family, has become a potential molecular target for the prevention and treatment of various cardiovascular diseases, such as DOX cardiomyopathy and heart failure. PARP-1 and PARP-2 share 69% homology in the catalytic regions. However, they do not entirely overlap in function. The role of PARP-2 in cardiovascular diseases, especially in DOX-induced cardiomyocyte aging, is less studied. In this study, we found for the first time that down-regulation of PARP-2 can inhibit DOX-induced cellular aging in cardiomyocytes. On the contrary, overexpression of PARP-2 can aggravate DOX-induced cardiomyocyte aging and injury. Further research showed that PARP-2 inhibited the expression and activity of SIRT1, which in turn was involved in the development of DOX-induced cardiomyocyte aging and injury. Our findings provide a preliminary experimental basis for establishing PARP-2 as a new target for preventing and treating DOX cardiomyopathy and related drug development.

Keywords: Aging; Doxorubicin; Inflammation; Oxidative stress; PARP-2; SIRT1.