Trichostatin a modulates intracellular reactive oxygen species through SOD2 and FOXO1 in human bone marrow‐mesenchymal stem cells

Abstract

Engraft cells are often exposed to oxidative stress and inflammation; therefore, any factor that can provide the stem cells resistance to these stresses may yield better efficacy in stem cell therapy. Studies indicate that histone deacetylase (HDACs) inhibitors alleviate damage induced by oxidative stress. In this study, we investigated whether regulation of reactive oxygen species (ROS) occurs through the HDAC inhibitor trichostatin A (TSA) in human bone marrow-mesenchymal stem cells (hBM-MSCs). Intracellular ROS levels increased following exposure to hydrogen peroxide (H2 O2 ), and were suppressed by TSA treatment. Levels of the antioxidant enzyme superoxide dismutase 2 (SOD2) increased following treatment with 200 nM TSA and to a lesser level at 1-5 μM TSA. Cell protective effects against oxidative stress were significantly increased in TSA-MSCs after treatment with low doses of TSA (50-500 nM) and decreased with high doses of TSA (5-10 μM). Consistent results were obtained with immunoblot analysis for caspase3. Investigation of Forkhead box O1 (FOXO1), superoxide dismutase 2 (SOD2), and p53 levels to determine intracellular signaling by TSA in oxidative stress-induced MSCs demonstrated that expression of phosphorylated-FOXO1 and phosphorylated-SOD2 decreased in H2 O2 -treated MSCs while levels of p53 increased. These effects were reversed by the treatment of 200 nM TSA. These results suggest that the main function of ROS modulation by TSA is activated through SOD2 and FOXO1. Thus, optimal treatment with TSA may protect hBM-MSCs against oxidative stress.

Functional restoration of replicative senescent mesenchymal stem cells by the brown alga Undaria pinnatifida

“…Antioxidant enzymes such as SOD1, SOD2, and catalase are known as major scavengers of iROS (Johnson & Giulivi 2005 ). Expression of these enzymes is decreased in cells exposed to excessive oxidative stress, resulting in the accumulation of iROS (Huang & Tindall 2007 ; Jeong & Cho 2015b ). Since we have shown that UP-Ex pretreatment protects against oxidative stress in hBM-MSCs, it is reasonable to assume that this protection is due to moderated iROS levels.…”

Trichostatin A Modulates Angiotensin II-induced Vasoconstriction and Blood Pressure Via Inhibition of p66shc Activation

“…HDAC inhibition reduced the production of ROS in cardiomyoblasts exposed to hypoxia/reoxygenation [ 29 ]. Recently, it was also shown that the intracellular increase of ROS levels following exposure to hydrogen peroxide was suppressed by TSA [ 30 ].…”

Opportunities and challenges of radiotherapy for treating cancer

“…Not surprisingly, multiple end points for HDAC-inhibitor activity have been reported, including gene expression, cell-cycle arrest, cell differentiation, antiangiogenesis, cell death, and autophagy. 81 In addition, HDAC inhibitors have been reported to generate ROS and modulate redox levels in cells, [82][83][84][85][86][87] resulting in DNA damage and activation of the DDR. 88,89 Others have shown that key DNA-repair molecules including Ku70/Ku80, DNA-PK, RAD50, RAD51, BRCA1/2, and MRE11 are downregulated by vorinostat and other HDAC inhibitors in combination with radiotherapy, leading to RIF persistence.…”