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.

Lithocarpus�polystachyus Rehd. leaves aqueous extract protects against hydrogen peroxide‑induced SH-SY5Y cells injury through activation of Sirt3 signaling pathway

“…Furthermore, the present findings indicated that H 2 O 2 decreased Sirt3, Foxo3a and SOd2 expressions, which was consistent with the theory that oxidative stress downregulates Foxo3a and SOd2, which are the two main substrates of Sirt3 (32,33). However, these effects were abolished by pre-treatment with ST, suggesting that ST activated Sirt3, thereby regulating Foxo3a directly and elevating SOd2 activity, which is mainly regulated by the mitochondrial sirtuin to eliminate excessive ROS (34).…”

Retracted: MicroRNA‐132 protects H9c2 cells against oxygen and glucose deprivation‐evoked injury by targeting FOXO3A

“…In addition, FOXO3A has been also reported to upregulate antioxidant enzymes to resist oxidative stress (Gurkar et al, ). Guo et al () illuminated that trichostatin A could relieve oxidative stress‐evoked myocardial injury via regulating FOXO3A. Nevertheless, whether FOXO3A is involved in adjusting OGD‐evoked injury in H9c2 cells is still ambiguous.…”

Luteolin improves heart preservation through inhibiting hypoxia‑dependent L‑type calcium channels in cardiomyocytes

“…Therefore, heart damage may be positively associated with storage duration and luteolin may be involved in reducing myocardial damage during long-term storage. By contrast, SOD activity, which is negatively associated with cell damage (25), increased after 12 an 18 h of storage in all three luteolin groups in what appeared to be a dose-dependent manner (Fig. 9E).…”