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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 26, 2005; DOI: 10.1124/jpet.105.090456

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Received for publication June 8, 2005.
Revised July 21, 2005.
Accepted for publication July 21, 2005.

EFFECTS OF PHYTOESTROGENS GENISTEIN AND DAIDZEIN ON PROSTACYCLIN PRODUCTION BY HUMAN ENDOTHELIAL CELLS

Carlos Hermenegildo 1*, Pilar J Oviedo 2, Miguel Angel Garcia-Perez 1, Juan J Tarin 2, Antonio Cano 2

1 Hospital Clinico Universitario de Valencia 2 Universitat de Valencia

* Address correspondence to: E-mail: carlos.hermenegildo{at}uv.es

Abstract

The molecular mechanisms of the vascular effects of phytoestrogens are poorly studied. Prostacyclin is a potent vasodilator synthesized by two isoforms of cyclooxygenase (COX) in endothelium. This study examine the effects of two phytoestrogens, the isoflavones genistein and daidzein, on prostacyclin production by cultured human umbilical vein endothelial cells (HUVEC) and the possible role of not only estrogen receptors but also both COX isoforms. The two phytoestrogens significantly increased prostacyclin release in a time- and dose-dependent (0.01-1 µM) manner, being higher than control after 24 hours. Selective inhibitors of COX-1, SC-560 and COX-2, NS-398, were used to investigate the relative contribution of each enzyme. Both inhibitors decreased basal production of prostacyclin, but only COX-2 inhibition completely abolished the isoflavone-stimulated prostacyclin production. Phytoestrogens also increased COX-2 mRNA expression and protein content, without affecting COX-1 levels. All these effects were mediated through estrogen receptor activation, since treatment of cells with the estrogen receptor antagonist ICI 182780 completely abolished the isoflavone-induced increase in prostacyclin production, COX-2 mRNA expression and COX-2 protein content. The results clearly support the hypothesis that genistein and daidzein increased HUVEC prostacyclin production through estrogen receptor-dependent mechanism, which involved the enhancement of COX-2 protein and activity.


Key words: cyclooxygenase, endothelium, hormone therapy, isoflavones, prostacyclin, vasodilator


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