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Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress
Tomczyk, Mateusz M.1,2,3; Cheung, Kyle G.1,2,3; Xiang, Bo1,2,3; Tamanna, Nahid4; Fonseca Teixeira, Ana L.4; Agarwal, Prasoon1,2,3,5,6; Kereliuk, Stephanie M.1,2,3; Spicer, Victor3,7,8; Lin, Ligen9,10; Treberg, Jason4; Tong, Qiang9; Dolinsky, Vernon W.1,2,3
2022-04-14
Source PublicationCirculation. Heart failure
ISSN1941-3289
Volume15Issue:5
Abstract

BACKGROUND: High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins. METHODS: Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). Mass spectrometry was performed on cardiac mitochondrial peptides in saline (n=6) and doxorubicin (n=5) treated hearts. Validation was performed in doxorubicin treated primary rat and human induced stem cell derived cardiomyocytes transduced with adenoviruses for M3-SIRT3 and M1-SIRT3 and deacetylase deficient mutants (n=4-10). RESULTS: Echocardiography revealed that M3-SIRT3 transgenic mice were partially resistant to doxorubicin induced changes to cardiac structure and function whereas M1-SIRT3 expression prevented cardiac remodeling and dysfunction. In doxorubicin hearts, 37 unique acetylation sites on mitochondrial proteins were altered. Pathway analysis revealed these proteins are involved in energy production, fatty acid metabolism, and oxidative stress resistance. Increased M1-SIRT3 expression in primary rat and human cardiomyocytes attenuated doxorubicin-induced superoxide formation, whereas deacetylase deficient mutants were unable to prevent oxidative stress. CONCLUSIONS: Doxorubicin reduced SIRT3 expression and markedly affected the cardiac mitochondrial acetylome. Increased M1-SIRT3 expression in vivo prevented doxorubicin-induced cardiac dysfunction, suggesting that SIRT3 could be a potential therapeutic target for mitigating doxorubicin-induced dilated cardiomyopathy.

KeywordAcetylation Dilated Cardiomyopathy Doxorubicin Mitochondria Superoxide
DOI10.1161/CIRCHEARTFAILURE.121.008547
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaCardiovascular System & Cardiology
WOS SubjectCardiac & Cardiovascular Systems
WOS IDWOS:000793999900002
Scopus ID2-s2.0-85130646204
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Cited Times [WOS]:2   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorTong, Qiang; Dolinsky, Vernon W.
Affiliation1.P.A., S.M.K., Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba' Winnipeg' Canada (M.M.T.,
2.Department of Pharmacology and Therapeutics (M.M.T., P.A., S.M.K., University of Manitoba, Winnipeg, Canada
3.Rady Faculty of Health Science, College of Medicine (M.M.T., P.A., S.M.K., V.S., University of Manitoba, Winnipeg, Canada
4.Department of Biological Sciences (N.T., University of Manitoba, Winnipeg, Canada
5.KTH Royal Institute of Technology, School of Electrical Engineering and Computer Science, Sweden
6.Science for Life Laboratory, Solna, Sweden
7.Department of Internal Medicine (V.S.), University of Manitoba, Winnipeg, Canada
8.Manitoba Center for Proteomics and Systems Biology, Winnipeg, Canada
9.Children's Nutrition Research Center, Baylor College of Medicine, Houston,
10.Institute of Chinese Medical Sciences, University of Macau, China (L.L.), China
Recommended Citation
GB/T 7714
Tomczyk, Mateusz M.,Cheung, Kyle G.,Xiang, Bo,et al. Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress[J]. Circulation. Heart failure,2022,15(5).
APA Tomczyk, Mateusz M.,Cheung, Kyle G.,Xiang, Bo,Tamanna, Nahid,Fonseca Teixeira, Ana L.,Agarwal, Prasoon,Kereliuk, Stephanie M.,Spicer, Victor,Lin, Ligen,Treberg, Jason,Tong, Qiang,&Dolinsky, Vernon W..(2022).Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress.Circulation. Heart failure,15(5).
MLA Tomczyk, Mateusz M.,et al."Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress".Circulation. Heart failure 15.5(2022).
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