title: Tibolone activates nitric oxide synthesis in human endothelial cells.
abstract: After the unexpected findings of the Women's Health Initiative trial, indicating that traditional cardiovascular risk markers fail to predict the effects of hormone replacement therapy, it is of interest to characterize how steroids act on vascular cells. This is particularly important for tissue-specific drugs such as tibolone, whose actions may differ from other preparations. Because nitric oxide (NO) is a key regulator of vascular tone and atherogenesis, we studied its regulation by tibolone and its metabolites on human endothelial cells. Tibolone and its estrogenic metabolites (3alpha- and 3beta-OH tibolone) activate NO synthesis by recruiting functional estrogen receptors, whereas the progestogenic/androgenic metabolite (Delta(4) isomer) has no effect. During prolonged exposures, tibolone and the estrogenic compounds enhance the expression of endothelial NO synthase (eNOS). In addition, tibolone is able to induce rapid activation of eNOS, leading to rapid increases in the release of NO. Relevant for its clinical effects, the sulfated metabolites of tibolone are also effective in activating eNOS. Different from estrogen, rapid activation of eNOS does not rely on recruitment of phosphatidylinositol-3 kinase but rather on MAPK-dependent cascades. These results help to understand the mechanisms of action of tibolone on the cardiovascular system and have relevant clinical implications.
authors.affiliation: Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma, 57, 56100 Pisa, Italy. t.simoncini@obgyn.med.unipi.it
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.forename: Paolo
authors.initials: P
authors.lastname: Mannella
authors.forename: Letizia
authors.initials: L
authors.lastname: Fornari
authors.forename: Antonella
authors.initials: A
authors.lastname: Caruso
authors.forename: Gaetano
authors.initials: G
authors.lastname: Varone
authors.forename: Silvia
authors.initials: S
authors.lastname: Garibaldi
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Genazzani
mesh_terms: D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020249:Hormone Replacement Therapy; D006801:Humans; D020935:MAP Kinase Signaling System; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009652:Norpregnenes / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D011960:Receptors, Estrogen / Q000502:physiology
chemical_list: D008076:Cholesterol, HDL; D009652:Norpregnenes; D011960:Receptors, Estrogen; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; C027385:tibolone