Abstract

The activation of peroxisome proliferator-activated receptor (PPAR)gamma is known to inhibit angiogenesis. As a potential mechanism for this, we aimed at examining the effects of PPARgamma agonists on the pro-angiogenic enzyme cyclooxygenase (COX)-2 in human endothelium. METHODS AND RESULTS: Cultured endothelial cells were pre-incubated with the PPARgamma 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 PPARgamma antagonists bisphenol A diglycidyl ether and GW9662 as well as by PPARgamma 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, PPARgamma agonists attenuated CREB activation. As both protein kinase C (PKC)alpha and beta 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 PKCalpha membrane translocation. CONCLUSION: VEGF induces CREB-mediated COX-2 expression through a PKCalpha-dependent pathway in human endothelium. The anti-angiogenic effect of PPARgamma agonists is due, at least in part, to an interference with the VEGF-stimulated PKCalpha-mediated activation of CREB and the related expression of COX-2

Autore Pugliese

• Carluccio Maria Annunziata , Massaro Marika

Tutti gli autori

• Scoditti E.; Massaro M.; Carluccio M. A.; Distante A.; Storelli C.; De Caterina R.

Titolo volume/Rivista

Cardiovascular research

Anno di pubblicazione

2010

ISSN

0008-6363

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

Non Disponibile

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile