on November 29, 2004
Published online before print November 29, 2004, doi: 10.1161/01.ATV.0000151648.58516.eb
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Submitted on June 2, 2004
Accepted on November 12, 2004
Cytochrome P4502C9-Derived Epoxyicosatrienoic Acids Induce the Expression of Cyclooxygenase-2 in Endothelial Cells
U. Ruth Michaelis ;
From the Institut für Kardiovaskuläre Physiologie (U.R.M., R.B., I.F.) and Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie and ZAFES (R.S.), Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; Department of Biochemistry (J.R.F.), University of Texas Southwestern Medical Center, Dallas, Tex.
* To whom correspondence should be addressed. E-mail: fleming{at}em.uni-frankfurt.de.
Objective-- Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to epoxyicosatrienoic acids (EETs). CYP2C9-derived EETs elicit endothelial cell proliferation and angiogenesis, but the signaling pathways involved are incompletely understood. Because cyclooxygenase-2 (COX-2) is involved in angiogenesis, we determined whether a link exists between CYP2C9 and COX-2 expression.
Methods and Results-- Human umbilical vein endothelial cells were infected with CYP2C9 sense or antisense adenoviral constructs. Overexpression of CYP2C9 increased COX-2 promoter activity, an effect accompanied by a significant increase in COX-2 protein expression and elevated prostacyclin production. The CYP2C9-induced expression of COX-2 was inhibited by the CYP2C9 inhibitor, sulfaphenazole, whereas 11,12-EET increased COX-2 expression. Overexpression of CYP2C9 and stimulation with 11,12-EET increased intracellular cAMP levels and stimulated DNA-binding of the cAMP-response element-binding protein. The protein kinase A inhibitor, KT5720, attenuated the CYP2C9-induced increase in COX-2 promoter activity and protein expression. Overexpression of CYP2C9 stimulated endothelial tube formation, an effect that was attenuated by the COX-2 inhibitor celecoxib. Identical responses were observed in cells preconditioned by cyclic strain to increase CYP2C expression.
Conclusion-- These data indicate that CYP2C9-derived EETs induce the expression of COX-2 in endothelial cells via a cAMP-dependent pathway and that this mechanism contributes to CYP2C9-induced angiogenesis.
Key words: angiogenesis • endothelium • gene expression • prostacyclin • cytochrome P450
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