RT Journal Article
SR Electronic
T1 Inactivation of Foxo3a and Subsequent Downregulation of PGC-1α Mediate Nitric Oxide-Induced Endothelial Cell Migration
JF Molecular and Cellular Biology
JO Mol. Cell. Biol.
FD American Society for Microbiology
SP 4035
OP 4044
DO 10.1128/MCB.00175-10
VO 30
IS 16
A1 Borniquel, Sara
A1 García-Quintáns, Nieves
A1 Valle, Inmaculada
A1 Olmos, Yolanda
A1 Wild, Brigitte
A1 Martínez-Granero, Francisco
A1 Soria, Estrella
A1 Lamas, Santiago
A1 Monsalve, María
YR 2010
UL http://mcb.asm.org/content/30/16/4035.abstract
AB In damaged or proliferating endothelium, production of nitric oxide (NO) from endothelial nitric oxide synthase (eNOS) is associated with elevated levels of reactive oxygen species (ROS), which are necessary for endothelial migration. We aimed to elucidate the mechanism that mediates NO induction of endothelial migration. NO downregulates expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which positively modulates several genes involved in ROS detoxification. We tested whether NO-induced cell migration requires PGC-1α downregulation and investigated the regulatory pathway involved. PGC-1α negatively regulated NO-dependent endothelial cell migration in vitro, and inactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which is activated by NO, reduced NO-mediated downregulation of PGC-1α. Expression of constitutively active Foxo3a, a target for Akt-mediated inactivation, reduced NO-dependent PGC-1α downregulation. Foxo3a is also a direct transcriptional regulator of PGC-1α, and we found that a functional FoxO binding site in the PGC-1α promoter is also a NO response element. These results show that NO-mediated downregulation of PGC-1α is necessary for NO-induced endothelial migration and that NO/protein kinase G (PKG)-dependent downregulation of PGC-1α and the ROS detoxification system in endothelial cells are mediated by the PI3K/Akt signaling pathway and subsequent inactivation of the FoxO transcription factor Foxo3a.