Genomic and nongenomic mechanisms of nitric oxide synthesis induction in human endothelial cells by a fourth-generation selective estrogen receptor modulator.
Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. EM-652 (acolbifene) is a fourth-generation selective ER modulator (SERM) exerting complete antiestrogenic effects on the breast and uterus. EM-652 potently inhibits bone resorption and induces positive lipid modifications in estrogen-deficient animals. As most of the cardioprotective actions of estrogen are exerted directly at the vascular level, we studied the effects of EM-652 on endothelial production of nitric oxide (NO) in vitro and in vivo. EM-652 triggers NO release by human umbilical vein endothelial cells through nongenomic mechanisms, rapidly activating endothelial nitric oxide synthase (eNOS) via an ER-dependent sequential activation of MAPKs and PI3K/Akt pathways independently from gene transcription or protein synthesis. Moreover, EM-652 increases eNOS protein levels during prolonged treatments. Upon pharmacological comparison, EM-652 is markedly more potent than the SERMs raloxifene and tamoxifen in increasing NO synthesis from endothelial cells. In ovariectomized and fertile rats, EM-652 increases aortic eNOS expression and enzymatic activity at low, but not at higher, dosages. The present data show that EM-652 (acolbifene) has estrogen-like activity on the vascular wall, directly increasing NO production through genomic and nongenomic mechanisms in vitro and in vivo.
Simoncini
Tommaso
T
Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, 56100 Pisa, Italy. t.simoncini@obgyn.med.unipi.it
Varone
Gaetano
G
Fornari
Letizia
L
Mannella
Paolo
P
Luisi
Michele
M
Labrie
Fernand
F
Genazzani
Andrea R
AR
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006801:Humans; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000235:genetics*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*
D020536:Enzyme Activators; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; D009569:Nitric Oxide; C012121:ritetronium; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020928:Mitogen-Activated Protein Kinases