Raloxifene acutely stimulates nitric oxide release from human endothelial cells via an activation of endothelial nitric oxide synthase.

Abstract

Raloxifene is a selective estrogen receptor modulator (SERM) clinically effective for the prevention of postmenopausal osteoporosis. Estrogen's effect on cardiovascular diseases is mainly dependent on direct actions on the vascular wall. Since raloxifene has an endothelium-dependent relaxing effect, we studied the effects of this molecule on nitric oxide (NO) release from cultured human umbilical vein endothelial cells. Clinically effective concentrations of the compound triggered a rapid and dose-dependent release of NO from endothelial cells. Raloxifene-induced NO production was dependent on an estrogen receptor-mediated mechanism, since it was abolished by the pure estrogen receptor antagonist ICI 182,780. Treatment of endothelial monolayers with raloxifene was not associated with changes in endothelial nitric oxide synthase (eNOS) messenger RNA or protein, showing that raloxifene does not increase NO release through a transcriptional increase of eNOS. Indeed, raloxifene-induced NO production is due to an estrogen receptor-dependent acute stimulation of eNOS enzymatic activity. In conclusion, raloxifene activates eNOS in human endothelial cells, exerting a potentially important direct vasculo-protective effect stimulating endothelial NO production.