MST1 mediates doxorubicin-induced cardiomyopathy by SIRT3 downregulation.
Anthracyclines
Cardiomyopathy
Cardioncology
Cardiotoxicity
Heart failure
Hippo pathway
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
11 Aug 2023
11 Aug 2023
Historique:
received:
26
03
2023
accepted:
16
07
2023
revised:
30
06
2023
medline:
16
8
2023
pubmed:
11
8
2023
entrez:
11
8
2023
Statut:
epublish
Résumé
Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.
Identifiants
pubmed: 37566283
doi: 10.1007/s00018-023-04877-7
pii: 10.1007/s00018-023-04877-7
pmc: PMC10421787
doi:
Substances chimiques
Sirtuin 3
EC 3.5.1.-
Doxorubicin
80168379AG
SIRT3 protein, human
EC 3.5.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
245Subventions
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PRIN 2017N8K7S2
Organisme : Sapienza Università di Roma
ID : RG120172B9E42E2C
Organisme : Sapienza Università di Roma
ID : RG11816433FC0145
Organisme : Sapienza Università di Roma
ID : AR11715C81FCFF6E
Organisme : Istituto Pasteur-Fondazione Cenci Bolognetti
ID : Grant Under 45
Organisme : Istituto Pasteur-Fondazione Cenci Bolognetti
ID : 2019 Call
Organisme : Ministero della Salute
ID : PNRR-MAD-2022-12376632
Organisme : European Union - NextGenerationEU
ID : PNRR-PE0000019-HEAL ITALIA
Informations de copyright
© 2023. The Author(s).
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