title: Tamoxifen elicits atheroprotection through estrogen receptor α AF-1 but does not accelerate reendothelialization.
abstract: Based on both experimental and clinical data, tamoxifen has been proposed to have cardiovascular benefits, although the mechanism(s) contributing to that protective effect are still poorly understood. In vitro experiments demonstrated that tamoxifen elicits its transcriptional effect through estrogen receptor (ER) α, but other targets can participate in its actions. However, although tamoxifen selectively activates the activating function (AF)-1 of ERα, we recently showed that this ERα subfunction is dispensable for the atheroprotective action of 17β-estradiol (E2), the main ligand of ERs. The goal of the present work is to determine to which extent ERα and its AF-1 mediate the vasculoprotective action of tamoxifen. Our data confirm that tamoxifen exerts an atheroprotective action on low density lipoprotein receptor (LDL-r(-/-)) female mice, but, in contrast to E2, it fails to accelerate reendothelialization after carotid electric injury. Tamoxifen and E2 elicit differences in gene expression profiles in the mouse aorta. Finally, the atheroprotective action of tamoxifen is abrogated in ERα(-/-)LDL-r(-/-) mice and in LDL-r(-/-) mice selectively deficient in ERαAF-1 (ERαAF-1(0/0)LDL-r(-/-)). Our results demonstrate, for the first time to our knowledge, that tamoxifen mediates its actions in vivo through the selective activation of ERαAF-1, which is sufficient to prevent atheroma, but not to accelerate endothelial healing.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1048, Institute of Metabolic and Cardiovascular Diseases, University of Toulouse 3, Toulouse, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Fontaine
authors.forename: Anne
authors.initials: A
authors.lastname: Abot
authors.forename: Audrey
authors.initials: A
authors.lastname: Billon-Galés
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.forename: Hortense
authors.initials: H
authors.lastname: Bergès
authors.forename: Etienne
authors.initials: E
authors.lastname: Grunenwald
authors.forename: Alexia
authors.initials: A
authors.lastname: Vinel
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Valera
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects; D020212:Carotid Artery Injuries; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056918:Nuclear Receptor Coactivators / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000517:prevention & control*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D047628:Estrogen Receptor alpha; D056918:Nuclear Receptor Coactivators; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen