RRC ID |
57378
|
著者 |
Cai W, Fujita T, Hidaka Y, Jin H, Suita K, Shigeta M, Kiyonari H, Umemura M, Yokoyama U, Sadoshima J, Ishikawa Y.
|
タイトル |
Translationally controlled tumor protein (TCTP) plays a pivotal role in cardiomyocyte survival through a Bnip3-dependent mechanism.
|
ジャーナル |
Cell Death Dis
|
Abstract |
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.
|
巻・号 |
10(8)
|
ページ |
549
|
公開日 |
2019-7-18
|
DOI |
10.1038/s41419-019-1787-7
|
PII |
10.1038/s41419-019-1787-7
|
PMID |
31320615
|
PMC |
PMC6639386
|
MeSH |
Animals
Apoptosis / drug effects
Apoptosis / genetics
Autophagy / drug effects
Autophagy / genetics
Biomarkers, Tumor / antagonists & inhibitors
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Cell Survival / genetics*
Cells, Cultured
Doxorubicin / toxicity
Heart Failure / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria / drug effects
Mitochondria / genetics
Mitochondria / metabolism*
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism*
Myocytes, Cardiac / metabolism*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Rats
Rats, Wistar
Tumor Protein, Translationally-Controlled 1
|
IF |
5.959
|
引用数 |
2
|
リソース情報 |
実験動物マウス |
RBRC01361 |