Translationally controlled tumor protein (TCTP) plays a pivotal role in cardiomyocyte survival through a Bnip3-dependent mechanism.

Wenqian Cai, Takayuki Fujita, Yuko Hidaka, Huiling Jin, Kenji Suita, Mayo Shigeta, Hiroshi Kiyonari, Masanari Umemura, Utako Yokoyama, Junichi Sadoshima, Yoshihiro Ishikawa

Cell death & disease 2019 Jul 18

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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.

Citation

Wenqian Cai, Takayuki Fujita, Yuko Hidaka, Huiling Jin, Kenji Suita, Mayo Shigeta, Hiroshi Kiyonari, Masanari Umemura, Utako Yokoyama, Junichi Sadoshima, Yoshihiro Ishikawa. Translationally controlled tumor protein (TCTP) plays a pivotal role in cardiomyocyte survival through a Bnip3-dependent mechanism. Cell death & disease. 2019 Jul 18;10(8):549