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Inactivation of Foxo3a and subsequent downregulation of PGC-alpha mediates nitric oxide induced endothelial cell migration

AuthorsBorniquel, Sara; García-Quintans, Nieves CSIC; Valle, Inmaculada; Olmos, Yolanda; Wild, Brigitte; Martínez-Granero, Francisco; Soria, Estrella; Lamas Peláez, Santiago CSIC ORCID ; Monsalve, María CSIC ORCID
Issue Date2010
CitationXXXIII Congreso SEBBM (2010)
AbstractIn 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 gamma-coactivator 1alpha (PGC-1alpha), which positively modulates several genes involved in ROS detoxification. We tested whether NO-induced cell migration requires PGC-1alpha downregulation and investigated the regulatory pathway involved. PGC-1alpha 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-1alpha. Expression of constitutively active Foxo3a, a target for Akt-mediated inactivation, reduced NO-dependent PGC-1alpha down-regulation. Foxo3a is also a direct transcriptional regulator of PGC-1alpha, and we found that a functional FoxO binding site in the PGC-1alpha promoter is also a NO response element. These results show that NO-mediated downregulation of PGC-1alpha is necessary for NO-induced endothelial migration, and that NO/PKG-dependent downregulation of PGC-1alpha and the ROS detoxification system in endothelial cells is mediated by the PI3K/Akt signaling pathway and subsequent inactivation of the FoxO transcription factor Foxo3a.
DescriptionResumen del trabajo presentado al XXXIII Congreso de la Sociedad Española de Bioquimica y Biología Molecular, celebrado en Córdoba del 14 al 17 de septiembre de 2010.
Appears in Collections:(IIBM) Comunicaciones congresos
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