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

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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.

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The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

Abbreviations

DOX:

Doxorubicin

PARPs:

Poly (ADP-ribose) polymerases

DMEM:

Dulbecco’s modified eagle medium

FBS:

Fetal bovine serum

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

DCFH-DA:

2,7-Dichlorodihydrofluorescein diacetate

DAMPs:

Damage-associated molecular patterns

HE:

Hematoxylin-eosin

CCK-8:

Cell counting kit-8

γ-H2AX:

Phosphorylated histone H2AX

IVSd:

Interventricular septal thickness during diastole

IVSs:

Interventricular septal thickness during systole

LVIDd:

Left ventricular internal diameter during diastole

LVIDs:

Left ventricular internal diameter during systole

LVPWd:

Left ventricular posterior wall thickness during diastole

LVPWs:

Left ventricular posterior wall thickness during systole

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Funding

This research was supported by grants from the Guangzhou Basic and Applied Basic Research Project (No. 202102020199), the Medical Science and Technology research Foundation of Guangdong Province (No. A2022063), the Guangzhou Medical University Discipline Construction Project-Epigenetic Drug R&D Incubation Program (No. 02-410-2206311), the College Students’ Science and Technology Innovation Project of Guangzhou Medical University (No. 2021A073), Guangzhou Medical University Discipline Construction Project-Pharmacy Top Talent Training Undergraduate Program (No. 02-410-2206302, No. 02-410-2206296 ), and the open research from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital (No. 202201-205).

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Author notes

  1. Chaoming Huang and Xuan Zhang have contributed equally to this work.

Authors and 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

    Chaoming Huang, Xuan Zhang, Ao Shen, Yanhong Hou, Shuhan Gao, Yi Zeng, Jiayu Chen, Runxiang Lin, Yu Zhang & Yi Cai

  2. Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511500, Qingyuan, China

    Shulin Wang

  3. Department of Medical Genetics and Cell Biology, GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Tianfen Xu

  4. School of Public Health, Guangzhou Medical University, Guangzhou, 511436, China

    Yongwan Xie

  5. Research Center of Tea and Tea Culture, College of Agronomy, Jiangxi Agricultural University, Nanchang, 330045, China

    Chunpeng Wan

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  1. Chaoming Huang
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Contributions

Conception or design of the work: CH, XZ and YC; Data collection: SW, AS, SG, TX, YH, YX, YZ, JC, RL; Drafting the article and critical revision of the article: YZ, CW, YC; Final ap-proval of the version to be published: All authors and All authors reviewed the manuscript.

Corresponding authors

Correspondence to Yu Zhang, Chunpeng Wan or Yi Cai.

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All animal studies were approved by the Institutional Animal Care and Use Committee at Guangzhou Medical University (Protocol GY2020–059).

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Huang, C., Zhang, X., Wang, S. et al. PARP-2 mediates cardiomyocyte aging and damage induced by doxorubicin through SIRT1 Inhibition. Apoptosis 29, 816–834 (2024). https://doi.org/10.1007/s10495-023-01929-y

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