Translationally controlled tumor protein (TCTP) plays a pivotal role in cardiomyocyte survival through a Bnip3-dependent mechanism.
Animals
Apoptosis
/ drug effects
Autophagy
/ drug effects
Biomarkers, Tumor
/ antagonists & inhibitors
Cell Survival
/ genetics
Cells, Cultured
Doxorubicin
/ toxicity
Heart Failure
/ metabolism
Male
Membrane Proteins
/ genetics
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria
/ drug effects
Mitochondrial Proteins
/ genetics
Myocytes, Cardiac
/ metabolism
RNA, Small Interfering
/ genetics
Rats
Rats, Wistar
Tumor Protein, Translationally-Controlled 1
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
18 07 2019
18 07 2019
Historique:
received:
26
03
2019
accepted:
21
06
2019
revised:
10
06
2019
entrez:
20
7
2019
pubmed:
20
7
2019
medline:
6
8
2020
Statut:
epublish
Résumé
Prevention of cardiomyocyte death is an important therapeutic strategy for heart failure. In this study, we focused on translationally controlled tumor protein (TCTP), a highly conserved protein that is expressed ubiquitously in mammalian tissues, including heart. TCTP plays pivotal roles in survival of certain cell types, but its function in cardiomyocytes has not been examined. We aimed to clarify the role of TCTP in cardiomyocyte survival and the underlying mechanism. Here, we demonstrated that downregulation of TCTP with siRNA induced cell death of cardiomyocytes with apoptotic and autophagic features, accompanied with mitochondrial permeability transition pore (mPTP) opening. TCTP loss did not induce cell death of cardiac fibroblasts. Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) was found to mediate the TCTP-loss-induced cardiomyocyte death. In exploring the clinical significance of the TCTP expression in the heart, we found that DOX treatment markedly downregulated the protein expression of TCTP in cultured cardiomyocytes and in mouse heart tissue. Exogenous rescue of TCTP expression attenuated DOX-induced cardiomyocyte death. In mice, cardiomyocyte-specific overexpression of TCTP resulted in decreased susceptibility to DOX-induced cardiac dysfunction, accompanied with attenuated induction of Bnip3. Dihydroartemisinin, a pharmacological TCTP inhibitor, induced development of heart failure and cardiomyocyte death in control mice, but not in mice with cardiomyocyte-specific TCTP overexpression. Our findings revealed TCTP has a pivotal role in cardiomyocyte survival, at least in part through a Bnip3-dependent mechanism. TCTP could be considered as a candidate therapeutic target to prevent DOX-induced heart failure.
Identifiants
pubmed: 31320615
doi: 10.1038/s41419-019-1787-7
pii: 10.1038/s41419-019-1787-7
pmc: PMC6639386
doi:
Substances chimiques
BNIP3 protein, rat
0
BNip3 protein, mouse
0
Biomarkers, Tumor
0
Membrane Proteins
0
Mitochondrial Proteins
0
RNA, Small Interfering
0
Tpt1 protein, mouse
0
Tpt1 protein, rat
0
Tumor Protein, Translationally-Controlled 1
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
549Références
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