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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The Transactivating Function 1 Of Estrogen Receptor A Is Dispensable For The Vasculoprotective Actions Of 17β-estradiol
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The Transactivating Function 1 Of Estrogen Receptor A Is Dispensable For The Vasculoprotective Actions Of 17β-estradiol

机译：雌激素受体A的反式激活功能1对于17β-雌二醇的血管保护作用是必不可少的

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摘要

Full-length 66-kDa estrogen receptor α (ERα) stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal domain and AF-2 in the ligand binding domain. Another physiologically expressed 46-kDa ERa isoform lacks the N-terminal A/B domains and is consequently devoid of AF-1. Previous studies in cultured endothelial cells showed that the N-terminal A/B domain might not be required for estradiol (E2)-elicited NO production. To evaluate the involvement of ERa AF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ERa A/B domain in the mouse. In these ERαAF-1~0 mice, both basal endothelial NO production and reendothelialization process were increased by E2 administration to a similar extent than in control mice. Furthermore, exogenous E2 similarly decreased fatty streak deposits at the aortic root from both ovariectomized 18-week-old ERαAF-1~(+/+) LDLr~(-/-) (low-density li-poprotein receptor) and ERαAF-1~0 LDLr~(-/-) mice fed with a hyper-cholesterolemic diet. In addition, quantification of lesion size on en face preparations of the aortic tree of 8-month-old ovariectomized or intact female mice revealed that ERα AF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ERa AF-1 is not required for three major vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. Thus, selective ER modulators stimulating ERa with minimal activation of ERα AF-1 could retain benefular actions, while minimizing the sexual effects.
机译：全长66 kDa雌激素受体α（ERα）通过两个激活功能（AF）刺激靶基因转录，两个激活功能分别是N末端域的AF-1和配体结合域的AF-2。另一个生理表达的46 kDa ERa亚型缺少N端A / B结构域，因此没有AF-1。以前在培养的内皮细胞中进行的研究表明，雌二醇（E2）诱导的NO生成可能不需要N-末端A / B结构域。为了评估ERa AF-1参与E2的血管保护作用，我们在小鼠中产生了ERαA / B结构域的靶向缺失。在这些ERαAF-1〜0小鼠中，通过E2给药可增加基础内皮一氧化氮的产生和重新内皮化的过程，其程度与对照小鼠相似。此外，外源性E2同样减少了卵巢切除的18周龄ERαAF-1〜（+ / +）LDLr〜（-/-）（低密度脂蛋白受体）和ERαAF-1在主动脉根部的脂肪条纹沉积。 〜0 LDLr〜（-/-）小鼠饲喂高胆固醇饮食。此外，对8个月大的去卵巢或完整雌性小鼠的主动脉树的面部制剂的病灶大小进行量化显示，ERαAF-1对于内源性雌激素的抗动脉粥样硬化作用是必不可少的。我们得出结论，E2的三个主要血管保护作用不需要ERa AF-1，而E2对其生殖目标的作用则是必需的。因此，以最小的ERαAF-1激活来刺激ERa的选择性ER调节剂可以保留有益的作用，同时将性影响降至最低。

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    Audrey Billon-Gales; Coralie Fontaine; Cedric Filipe; Victorine Douin-Echinard; Marie-Jose Fouque; Gilles Flouriot; Pierre Gourdy; Francoise Lenfant; Henrik Laurell; Andree Krust; Pierre Chambon; Jean-Francois Arnal;

  • 作者单位

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Equipe Recepteur des Oestrogenes et Destinee Cellulaire, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 6026, Universite de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Institut de Medecine Moleculaire de Rangueil, Institut National de la Sante et de la Recherche Medicale, Unite 858, Universite Toulouse III Paul Sabatier, Centre Hospitalier Universitaire de Toulouse, 31432 Toulouse, France;

    Ins;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    atherosclerosis; reendothelialization; vasculoprotection;

    机译：动脉粥样硬化;血管内皮;血管保护;

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