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FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells

Item Type:Article
Title:FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells
Creators Name:Urbich, C. and Knau, A. and Fichtlscherer, S. and Walter, D.H. and Brühl, T. and Potente, M. and Hofmann, W.K. and de Vos, S. and Zeiher, A.M. and Dimmeler, S.
Abstract:Endothelial progenitor cells (EPCs) contribute to postnatal neovascularization. Risk factors for coronary artery disease reduce the number of EPCs in humans. Since EPC apoptosis might be a potential mechanism to regulate the number of EPCs, we investigated the effects of oxidative stress and HMG-CoA-reductase inhibitors (statins) on EPC apoptosis. Atorvastatin, mevastatin, or VEGF prevented EPC apoptosis induced by H2O2. The antiapoptotic effect was reversed by inhibition of the PI3K/Akt pathway. Forkhead transcription factors (FOXO1, FOXO3a, FOXO4) exert proapoptotic effects and are phosphorylated and, thereby, inactivated by Akt. Therefore, we elucidated the involvement of forkhead transcription factors. Atorvastatin induced the phosphorylation of the predominant forkhead factor FOXO4 in EPCs. In addition, atorvastatin reduced the expression of the proapoptotic forkhead-regulated protein Bim in a PI3K-dependent manner. Consistently, overexpression of FOXO4 activated the Bim promoter as determined by reporter gene expression and stimulated the expression of Bim, resulting in an increased EPC apoptosis. Statins failed to prevent EPC apoptosis induced by overexpression of Bim or nonphosphorylatable FOXO4, suggesting that the protective effects of statins depend on this pathway. In summary, our results show that FOXO-dependent expression of Bim plays a pivotal role for EPC apoptosis. Statins reduce oxidative stress-induced EPC apoptosis, inactivate FOXO4, and down-regulate Bim.
Keywords:Forkhead Transcription Factors, Cell Death, PI3K/Akt Signaling, Statins
Source:FASEB Journal
Publisher:Federation of American Societies for Experimental Biology
Page Range:974-976
Date:June 2005
Official Publication:https://doi.org/10.1096/fj.04-2727fje
PubMed:View item in PubMed

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