Journal article
Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity
Toxicology letters, Vol.275, pp.28-38
06/05/2017
DOI: 10.1016/j.toxlet.2017.04.018
PMID: 28456571
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.
Details
- Title: Subtitle
- Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity
- Creators
- Lan Cui - Academy of Military Medical SciencesJiabin Guo - Academy of Military Medical SciencesQiang Zhang - Emory UniversityJian Yin - Academy of Military Medical SciencesJin LiWei Zhou - Academy of Military Medical SciencesTingfen Zhang - Academy of Military Medical SciencesHaitao Yuan - Academy of Military Medical SciencesJun Zhao - Academy of Military Medical SciencesLi Zhang - Academy of Military Medical SciencesPaul L Carmichael - UnileverShuangqing Peng - Academy of Military Medical Sciences
- Resource Type
- Journal article
- Publication Details
- Toxicology letters, Vol.275, pp.28-38
- DOI
- 10.1016/j.toxlet.2017.04.018
- PMID
- 28456571
- ISSN
- 0378-4274
- eISSN
- 1879-3169
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81470167, 81430090; DOI: 10.13039/501100005090, name: Beijing Nova Program, award: Z171100001117103; name: AMMS Innovative Foundation, award: 2017CXJJ13; name: Unilever International Collaborative Project, award: MA-2015-00410
- Language
- English
- Date published
- 06/05/2017
- Academic Unit
- Neurology
- Record Identifier
- 9984302205802771
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