FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells.
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.
Urbich
Carmen
C
Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
Knau
Andrea
A
Fichtlscherer
Stephan
S
Walter
Dirk H
DH
Brühl
Thomas
T
Potente
Michael
M
Hofmann
Wolf K
WK
de Vos
Sven
S
Zeiher
Andreas M
AM
Dimmeler
Stefanie
S
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000502:physiology; D000069059:Atorvastatin; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007963:Leukocytes, Mononuclear; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D014471:Umbilical Veins
D051017:Apoptosis Regulatory Proteins; D000069059:Atorvastatin; D000072224:Bcl-2-Like Protein 11; D018797:Cell Cycle Proteins; D051858:Forkhead Transcription Factors; D006538:Heptanoic Acids; D006861:Hydrogen Peroxide; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D014157:Transcription Factors; C000606775:BCL2L11 protein, human; C108803:FOXO4 protein, human