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Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability
- Source :
- International Journal of Molecular Sciences; Volume 23; Issue 18; Pages: 10960
- Publication Year :
- 2022
-
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.
- Subjects :
- Catalysis
Inorganic Chemistry
Protein-Lysine 6-Oxidase
Estrogen Receptor beta
Humans
RNA, Messenger
Physical and Theoretical Chemistry
Molecular Biology
Spectroscopy
Tissue Inhibitor of Metalloproteinase-2
Tissue Inhibitor of Metalloproteinase-1
Estradiol
Tumor Necrosis Factor-alpha
Organic Chemistry
atherosclerosis
plaque vulnerability
estrogen
estrogen receptors
GPR-30
endothelial cells
matrix metalloproteinases MMPs
MCP-1
p21
Estrogen Receptor alpha
Endothelial Cells
Estrogens
General Medicine
Atherosclerosis
Plaque, Atherosclerotic
Computer Science Applications
Matrix Metalloproteinase 9
Receptors, Estrogen
Matrix Metalloproteinase 2
Transcriptome
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 23
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- International journal of molecular sciences
- Accession number :
- edsair.doi.dedup.....254baabe075f85d3e48bbde15219bb29