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.
Highlights
Prevention of cardiomyocyte death is an important therapeutic strategy for heart failure[1,2]
translationally controlled tumor protein (TCTP)-loss-induced cardiomyocyte death had apoptotic and autophagic features accompanied with mitochondrial permeability transition pore (mPTP) opening, which are features of Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3)-induced cell death[27,28,29]
TCTP downregulation resulted in cardiomyocyte death In order to investigate the role of TCTP in cardiomyocyte survival, we downregulated TCTP expression with two different siRNAs (TCTP siRNA #1 and #2) in neonatal rat ventricular myocytes (NRVMs)
Summary
Prevention of cardiomyocyte death is an important therapeutic strategy for heart failure[1,2]. To our knowledge, there is no report on TCTP function in cardiomyocytes. TCTP exerts its functions in a cell-type-dependent manner. It promotes cell survival and inhibits apoptosis in some types of normal cells[12,19] and cancer cells[15,20]. TCTP silencing caused induction of DNA damage or apoptosis in several normal[19] and cancer cell lines[22,23,24]. These findings indicate that TCTP is a pro-survival molecule. An inverse relationship between TCTP expression and growth rate was found with an epithelial cell line[26]
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