Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability

Narjes Nasiri-Ansari, Eliana Spilioti, Ioannis Kyrou, Vassiliki Kalotychou, Antonios Chatzigeorgiou, Despina Sanoudou, Karin Dahlman-Wright, Harpal S. Randeva, Athanasios G. Papavassiliou, Paraskevi Moutsatsou, Eva Kassi

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    Abstract

    In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

    Original languageEnglish
    Article number10960
    Number of pages23
    JournalInternational Journal of Molecular Sciences
    Volume23
    Issue number18
    DOIs
    Publication statusPublished - 19 Sept 2022

    Bibliographical note

    © 2022 by the authors.
    This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

    Funder

    This work was funded by the “ARISTEIA” program (Program’s code: 11897).

    Keywords

    • atherosclerosis
    • endothelial cells
    • estrogen
    • estrogen receptors
    • GPR-30
    • matrix metalloproteinases MMPs
    • MCP-1
    • p21
    • plaque vulnerability

    ASJC Scopus subject areas

    • Catalysis
    • Molecular Biology
    • Spectroscopy
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Inorganic Chemistry

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