Notch1 mediates visfatin-induced FGF-2 up-regulation and endothelial angiogenesis.

نویسندگان

  • Yun-Hee Bae
  • Hyun-Joo Park
  • Su-Ryun Kim
  • Jee-Young Kim
  • Youra Kang
  • Jung-Ae Kim
  • Hee-Jun Wee
  • Ryoichiro Kageyama
  • Jin Sup Jung
  • Moon-Kyoung Bae
  • Soo-Kyung Bae
چکیده

AIMS Our aims were to determine the role of Notch1 in mediating visfatin-induced angiogenesis and to explore potential target genes involved. METHODS AND RESULTS Inhibition of Notch signalling attenuated visfatin-induced angiogenesis in vitro, ex vivo, and in vivo. Visfatin increased γ-secretase activity, Notch1 cleavage and activation, and Hes1 gene induction. Visfatin also stimulated fibroblast growth factor-2 (FGF-2) gene expression in a Notch1-dependent manner. Enforced expression of active Notch1 intracellular domain increased FGF-2 protein levels and stimulated endothelial tube formation, whereas blocking Notch1 signalling or knockdown of Notch1 by small interfering RNA suppressed visfatin-induced FGF-2 up-regulation and angiogenesis. Reporter analysis of FGF-2 promoter revealed the presence of CSL (CBF-1, suppressor of hairless, LAG-1)-binding site, and chromatin immunoprecipitation analysis demonstrated the binding of Notch1-CSL complex to this site in response to visfatin. CONCLUSION Our data provide the first example of Notch1-dependent endothelial FGF-2 induction by visfatin and of Notch1 activation in visfatin-stimulated endothelial angiogenesis, suggesting that the signalling axis of visfatin/Notch1/angiogenic factors like FGF-2 might be a valuable target for pathological angiogenesis.

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عنوان ژورنال:
  • Cardiovascular research

دوره 89 2  شماره 

صفحات  -

تاریخ انتشار 2011