Hydrogen peroxide induced impairment of endothelial progenitor cell viability is mediated through a FoxO3a dependant mechanism

• Published in: Microvascular research 2013-11, Vol.90, p.48-54
• Main Authors: Wang, Fei, Wang, Yu-Qiang, Cao, Qing, Zhang, Jian-Jun, Huang, Li-Ya, Sang, Tian-Tian, Liu, Fang, Chen, Shu-Yan
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Humans; Hydrogen Peroxide - toxicity; Membrane Proteins - metabolism; Mutation; Neovascularization, Physiologic - drug effects; Oxidants - toxicity; Oxidative Stress - drug effects; Proto-Oncogene Proteins - metabolism; Signal Transduction - drug effects; Stem Cells - drug effects; Stem Cells - metabolism; Stem Cells - pathology; Transduction, Genetic; Transfection
• ISSN: 0026-2862; 1095-9319
• DOI: 10.1016/j.mvr.2013.07.009

Increased oxidative stress has been suggested to contribute to the functional impairment of endothelial progenitor cells (EPCs). The Forkhead box O transcription factors (FoxOs) are critical regulators involved in various cellular processes including cell apoptosis. Here, we investigated whether FoxOs are required in oxidative stress induced EPC apoptosis. EPCs were cultured from cord blood derived mononuclear cells and treated with hydrogen peroxide (H2O2) for induction of oxidative stress. Incubation with H2O2 dose dependently reduced viability and increased apoptosis in EPCs. Western blotting showed that EPCs predominantly expressed FoxO3a and the expression was markedly increased upon H2O2 treatment. Transduction with adenoviral vectors expressing either a wide-type or a non-phosphorylatable, constitutively active mutant of FoxO3a led to further increased apoptosis of EPCs after H2O2 treatment. Conversely, FoxO3a silencing rescued EPCs from these H2O2 induced deleterious effects. Overexpression of FoxO3a also increased the level of the pro-apoptotic protein Bim, whereas FoxO3a silencing downregulated H2O2 induced Bim expression. Furthermore, Matrigel assay demonstrated that FoxO3a overexpression significantly impaired the tube forming ability of EPCs, whereas its silencing completely protected EPCs from H2O2 induced decrease of capillary formation. These data suggest that oxidative stress induced impairment of EPC survival is mediated through a FoxO3a dependant mechanism, possibly by transcriptional regulation of Bim. Our data indicate FoxO3a as a potential therapeutic target for improvement of EPC number and function in patients with ischemic heart disease. •H2O2 impaired EPC survival and promoted EPC apoptosis.•H2O2 induced EPC apoptosis was dependent on FoxO3a.•FoxO3a mediated H2O2 induced Bim expression in EPCs.•H2O2 decreased tube forming ability of EPCs via a FoxO3a dependent mechanism.