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2017 ; 40
(4
): 999-1008
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Trichostatin A attenuates oxidative stress-mediated myocardial injury through the
FoxO3a signaling pathway
#MMPMID28849190
Guo Y
; Li Z
; Shi C
; Li J
; Yao M
; Chen X
Int J Mol Med
2017[Oct]; 40
(4
): 999-1008
PMID28849190
show ga
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 (??m) 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 ??m. 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.