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Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity.
Toxicol Lett. 2017 Jun 05; 275:28-38.TL

Abstract

The hormone erythropoietin (EPO) has been demonstrated to protect against chemotherapy drug doxorubicin (DOX)-induced cardiotoxicity, but the underlying mechanism remains obscure. We hypothesized that silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent protein deacetylase that activates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), plays a crucial role in regulating mitochondrial function and mediating the beneficial effect of EPO. Our study in human cardiomyocyte AC16 cells showed that DOX-induced cytotoxicity and mitochondrial dysfunction, as manifested by decreased mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential, and increased mitochondrial superoxide accumulation, can be mitigated by EPO pretreatment. EPO was found to upregulate SIRT1 activity and protein expression to reverse DOX-induced acetylation of PGC-1α and suppression of a suite of PGC-1α-activated genes involved in mitochondrial function and biogenesis, such as nuclear respiratory factor-1 (NRF1), mitochondrial transcription factor A (TFAM), citrate synthase (CS), superoxide dismutase 2 (SOD2), cytochrome c oxidase IV (COXIV), and voltage-dependent anion channel (VDAC). Silencing of SIRT1 via small RNA interference sensitized AC16 cells to DOX-induced cytotoxicity and reduction in mtDNA copy number. Although with SIRT1 silenced, EPO could reverse to some extent DOX-induced mitochondrial superoxide accumulation, loss of mitochondrial membrane potential and ATP depletion, it failed to normalize protein expression of PGC-1α and its downstream genes. Taken together, our results indicated that EPO may activate SIRT1 to enhance mitochondrial function and protect against DOX-induced cardiotoxicity.

Authors+Show Affiliations

Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: gjb321@163.com.Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.Unilever Safety and Environmental Assurance Center, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: pengsq@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28456571

Citation

Cui, Lan, et al. "Erythropoietin Activates SIRT1 to Protect Human Cardiomyocytes Against Doxorubicin-induced Mitochondrial Dysfunction and Toxicity." Toxicology Letters, vol. 275, 2017, pp. 28-38.
Cui L, Guo J, Zhang Q, et al. Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicol Lett. 2017;275:28-38.
Cui, L., Guo, J., Zhang, Q., Yin, J., Li, J., Zhou, W., Zhang, T., Yuan, H., Zhao, J., Zhang, L., Carmichael, P. L., & Peng, S. (2017). Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicology Letters, 275, 28-38. https://doi.org/10.1016/j.toxlet.2017.04.018
Cui L, et al. Erythropoietin Activates SIRT1 to Protect Human Cardiomyocytes Against Doxorubicin-induced Mitochondrial Dysfunction and Toxicity. Toxicol Lett. 2017 Jun 5;275:28-38. PubMed PMID: 28456571.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. AU - Cui,Lan, AU - Guo,Jiabin, AU - Zhang,Qiang, AU - Yin,Jian, AU - Li,Jin, AU - Zhou,Wei, AU - Zhang,Tingfen, AU - Yuan,Haitao, AU - Zhao,Jun, AU - Zhang,Li, AU - Carmichael,Paul L, AU - Peng,Shuangqing, Y1 - 2017/04/27/ PY - 2017/03/03/received PY - 2017/04/21/revised PY - 2017/04/25/accepted PY - 2017/5/1/pubmed PY - 2017/6/27/medline PY - 2017/5/1/entrez KW - Cardiotoxicity KW - Doxorubicin KW - Erythropoietin KW - Mitochondrial dysfunction KW - SIRT1 SP - 28 EP - 38 JF - Toxicology letters JO - Toxicol. Lett. VL - 275 N2 - The hormone erythropoietin (EPO) has been demonstrated to protect against chemotherapy drug doxorubicin (DOX)-induced cardiotoxicity, but the underlying mechanism remains obscure. We hypothesized that silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent protein deacetylase that activates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), plays a crucial role in regulating mitochondrial function and mediating the beneficial effect of EPO. Our study in human cardiomyocyte AC16 cells showed that DOX-induced cytotoxicity and mitochondrial dysfunction, as manifested by decreased mitochondrial DNA (mtDNA) copy number, mitochondrial membrane potential, and increased mitochondrial superoxide accumulation, can be mitigated by EPO pretreatment. EPO was found to upregulate SIRT1 activity and protein expression to reverse DOX-induced acetylation of PGC-1α and suppression of a suite of PGC-1α-activated genes involved in mitochondrial function and biogenesis, such as nuclear respiratory factor-1 (NRF1), mitochondrial transcription factor A (TFAM), citrate synthase (CS), superoxide dismutase 2 (SOD2), cytochrome c oxidase IV (COXIV), and voltage-dependent anion channel (VDAC). Silencing of SIRT1 via small RNA interference sensitized AC16 cells to DOX-induced cytotoxicity and reduction in mtDNA copy number. Although with SIRT1 silenced, EPO could reverse to some extent DOX-induced mitochondrial superoxide accumulation, loss of mitochondrial membrane potential and ATP depletion, it failed to normalize protein expression of PGC-1α and its downstream genes. Taken together, our results indicated that EPO may activate SIRT1 to enhance mitochondrial function and protect against DOX-induced cardiotoxicity. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/28456571/Erythropoietin_activates_SIRT1_to_protect_human_cardiomyocytes_against_doxorubicin_induced_mitochondrial_dysfunction_and_toxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(17)30168-6 DB - PRIME DP - Unbound Medicine ER -