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PPARγ agonists inhibit angiogenesis by suppressing PKCα- and CREB-mediated COX-2 expression in the human endothelium

Egeria Scoditti, Marika Massaro, Maria Annunziata Carluccio, Alessandro Distante, Carlo Storelli, Raffaele De Caterina
DOI: http://dx.doi.org/10.1093/cvr/cvp400 302-310 First published online: 23 December 2009


Aims The activation of peroxisome proliferator-activated receptor (PPAR)γ is known to inhibit angiogenesis. As a potential mechanism for this, we aimed at examining the effects of PPARγ agonists on the pro-angiogenic enzyme cyclooxygenase (COX)-2 in human endothelium.

Methods and results Cultured endothelial cells were pre-incubated with the PPARγ agonists rosiglitazone (RSG) or GW1929 before stimulation with vascular endothelial growth factor (VEGF) or phorbol myristate acetate (PMA). RSG and GW1929 attenuated VEGF- and PMA-stimulated COX-2 activity, as well as protein and mRNA expression. This effect was abolished by the PPARγ antagonists bisphenol A diglycidyl ether and GW9662 as well as by PPARγ small-interfering RNAs (siRNAs). Transient transfection experiments revealed that the induction of COX-2 promoter was significantly inhibited by RSG through an interference with the cAMP response element (CRE) site. COX-2 downregulation after siRNA targeting CRE-binding protein (CREB) confirmed the role of CREB in mediating COX-2 transcription. Correspondingly, PPARγ agonists attenuated CREB activation. As both protein kinase C (PKC)α and β are involved in VEGF-induced COX-2 expression and CREB activation, we investigated which isoform(s) of PKC was affected by RSG. RSG only reduced VEGF- and PMA-stimulated PKCα membrane translocation.

Conclusion VEGF induces CREB-mediated COX-2 expression through a PKCα-dependent pathway in human endothelium. The anti-angiogenic effect of PPARγ agonists is due, at least in part, to an interference with the VEGF-stimulated PKCα-mediated activation of CREB and the related expression of COX-2.

  • Angiogenesis
  • Cyclooxygenase-2
  • Gene expression
  • Protein kinase C
  • Growth factors
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