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Trichostatin A attenuates oxidative stress-mediated myocardial injury through the FoxO3a signaling pathway.

Abstract：

:Trichostatin A (TSA), a histone deacetylase inhibitor, is widely used as an anticancer drug. Recently, TSA has been shown to exert a protective effect on ischemia/reperfusion (I/R) injury; however, the underlying mechanisms remain unclear. Forkhead box O3a (FoxO3a), a unique FoxO family member, has been shown to attenuate myocardial injury by increasing resistance to oxidative stress in mice. The present study aimed to investigate whether TSA exerts its cardioprotective effects through the FoxO3a signaling pathway. For this purpose, healthy male Wistar rats were pre-treated with TSA for 5 days before they were subjected to ligation/relaxation of the left anterior descending branch of the coronary artery and to 30 min of ischemia, followed by 24 h of reperfusion. The activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and superoxide diamutase (SOD), as well as the malondialdehyde (MDA) levels were examined. The H9c2 rat myocardial cell line was cultured in 10% FBS-containing DMEM for 24 h. The cells were incubated with/without TSA (50 nmol/l) for 1 h and then incubated with/without H2O2 (400 µM) for 2 h. Reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) were measured by probe staining in the H9c2 cells. The expression of FoxO3a, mitochondrial SOD2 and catalase was quantified by western blot analysis. The levels of H3 and H4 acetylation of the FoxO3a promoter region were examined by chromatin immunoprecipitation assay. TSA significantly reduced the myocardial infarct size and the activities of serum LDH, AST and CK in the rats. TSA also decreased the levels of MDA and increased the activities of SOD in the myocardial tissue of the rats. Consistent with the reduced injury to the TSA-treated rats, TSA significantly reduced the H2O2-induced levels of ROS and increased Δψm. In addition, TSA increased the expression of FoxO3a, SOD2 and catalase, which may be related to increasing the level of H4 acetylation of the FoxO3a promoter region. Our results thus revealed that TSA protected the myocardium from oxidative stress-mediated damage by increasing H4 acetylation of the FoxO3a promoter region, and the expression of FoxO3a, SOD2 and catalase.

journal_name

Int J Mol Med

journal_title

International journal of molecular medicine

authors

Guo Y,Li Z,Shi C,Li J,Yao M,Chen X

doi

10.3892/ijmm.2017.3101

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

999-1008

issue

eissn

1107-3756

issn

1791-244X

journal_volume

pub_type

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Trichostatin A attenuates oxidative stress-mediated myocardial injury through the FoxO3a signaling pathway.