title: Activation function 2 (AF2) of estrogen receptor-alpha is required for the atheroprotective action of estradiol but not to accelerate endothelial healing.
abstract: 17β-Estradiol (E2) regulates estrogen receptor-α (ERα) target gene transcription through the two independent activation functions (AFs), AF1 and AF2, located in the N-terminal and ligand binding domain of ERα, respectively. We previously reported that ERα is required for the E2 atheroprotective action as well as for its accelerative action on endothelial healing, but its AF1 function is dispensable. Here, we investigated the role of ERαAF2 in these two major beneficial actions of E2 by electively targeting ERαAF2 (named ERαAF2(0)). Our results prove four points. (i) Compared with WT ERα, the ability of ERαAF2(0) to stimulate the C3 complement or the estrogen response element-thymidine kinase promoter in two cell lines was dramatically decreased, confirming the importance of AF2 in the E2-induced transcriptional activity of ERα. (ii) The uterotrophic action of E2 was totally absent in ERαAF2(0) mice, showing the crucial role of ERαAF2 in E2-induced uterus hyperplasia. (iii) ERαAF2 was dispensable for the accelerative action of E2 on endothelial healing, underlining the functionality of ERαAF2(0) in vivo. (iv) Finally, the atheroprotective effect of E2 was abrogated in ERαAF2(0) LDL-r(-/-) mice. Thus, whereas ERαAF1 and ERαAF2 are both required for the uterotrophic action of E2, we show that only ERαAF2 is necessary for its atheroprotective effect.
authors.affiliation: Université Paul Sabatier, Institut National de la Santé et de la Recherche Médicale U1048, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Billon-Galés
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Coralie
authors.initials: C
authors.lastname: Fontaine
authors.forename: Anne
authors.initials: A
authors.lastname: Abot
authors.forename: Gilles
authors.initials: G
authors.lastname: Flouriot
authors.forename: Céline
authors.initials: C
authors.lastname: Toutain
authors.forename: Hortense
authors.initials: H
authors.lastname: Berges
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
authors.forename: Pierre
authors.initials: P
authors.lastname: Gourdy
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D015203:Reproducibility of Results; D015533:Transcriptional Activation / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D047628:Estrogen Receptor alpha; D020011:Protective Agents; D004958:Estradiol