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Mitochondrial Sirtu...
Mitochondrial Sirtuin-3 (SIRT3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy by Modulating Protein Acetylation and Oxidative Stress
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- Tomczyk, Mateusz M. (författare)
- Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.
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- Cheung, Kyle G. (författare)
- Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.
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- Xiang, Bo (författare)
- Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.
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- Tamanna, Nahid (författare)
- Univ Manitoba, Dept Biol Sci, Winnipeg, MB, Canada.
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- Teixeira, Ana L. Fonseca (författare)
- Univ Manitoba, Dept Biol Sci, Winnipeg, MB, Canada.
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- Agarwal, Prasoon (författare)
- KTH,Beräkningsvetenskap och beräkningsteknik (CST),Science for Life Laboratory, SciLifeLab,Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.
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- Kereliuk, Stephanie M. (författare)
- Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.
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- Spicer, Victor (författare)
- Univ Manitoba, Dept Internal Med, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.;Manitoba Ctr Prote & Syst Biol, Winnipeg, MB, Canada.
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- Lin, Ligen (författare)
- Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA.;Univ Macau, Inst Chinese Med Sci, Taipa, Macao, Peoples R China.
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- Treberg, Jason (författare)
- Univ Manitoba, Dept Biol Sci, Winnipeg, MB, Canada.
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- Tong, Qiang (författare)
- Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA.
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- Dolinsky, Vernon W. (författare)
- Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada.;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada.
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Childrens Hosp Res Inst Manitoba, Diabet Res Envisioned & Accomplished Manitoba DRE, Winnipeg, MB, Canada;Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada.;Univ Manitoba, Coll Med, Rady Fac Hlth Sci, Winnipeg, MB, Canada. Univ Manitoba, Dept Biol Sci, Winnipeg, MB, Canada. (creator_code:org_t)
- Ovid Technologies (Wolters Kluwer Health), 2022
- 2022
- Engelska.
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Ingår i: Circulation Heart Failure. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3289 .- 1941-3297. ; 15:5
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Oto-rhino-laryngologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Otorhinolaryngology (hsv//eng)
Nyckelord
- acetylation
- dilated cardiomyopathy
- doxorubicin
- mitochondria
- superoxide
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Till lärosätets databas
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Tomczyk, Mateusz ...
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Cheung, Kyle G.
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Xiang, Bo
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Tamanna, Nahid
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Teixeira, Ana L. ...
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Agarwal, Prasoon
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visa fler...
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Kereliuk, Stepha ...
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Spicer, Victor
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Lin, Ligen
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Treberg, Jason
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Tong, Qiang
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Dolinsky, Vernon ...
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visa färre...
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