Nongenomic mechanisms of endothelial nitric oxide synthase activation by the selective estrogen receptor modulator raloxifene.

Abstract:

BACKGROUND:Nontranscriptional signaling through estrogen receptors (ERs) is important in the cardiovascular system. In particular, estrogen stimulates endothelial NO synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K) pathway. The selective estrogen receptor modulator (SERM) raloxifene is effective for the treatment of postmenopausal osteoporosis, but its ability to activate eNOS via PI3K is unknown. METHODS AND RESULTS:Human umbilical vein endothelial cells were cultured in estrogen-deprived, phenol red-free medium. Raloxifene stimulated eNOS in a concentration- and time-dependent manner. Activation of eNOS by raloxifene was blocked by the PI3K inhibitor wortmannin and by the ER antagonist ICI 182,780 but not by transcriptional or translational inhibitors. Coimmunoprecipitation studies demonstrated that, in a ligand-dependent manner, raloxifene increased ERalpha-associated p85alpha, p110alpha, and PI3K activity. This correlated temporally with increases in the serine and threonine phosphorylation and activation of protein kinase Akt. CONCLUSIONS:Our findings indicate that nongenomic ER signaling triggered by a SERM leads to a rapid activation of NO synthesis in human endothelial cells. The ability of raloxifene to facilitate ERalpha-PI3K interaction may provide additional insight into the structure-function relationship of specific SERMs, which promote the nontranscriptional effects of ER.

journal_name

Circulation

journal_title

Circulation

authors

Simoncini T,Genazzani AR,Liao JK

doi

10.1161/hc1102.105267

subject

Has Abstract

pub_date

2002-03-19 00:00:00

pages

1368-73

issue

11

eissn

0009-7322

issn

1524-4539

journal_volume

105

pub_type

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