Differential effect of estrogen receptor alpha and beta agonists on the receptor for advanced glycation end product expression in human microvascular endothelial cells.
Estrogens are known to induce the expression of the receptor for advanced glycation end products (RAGE). In the current investigation, we examined the effect of three estrogens with different potency for specific estrogen receptors (ER) on RAGE expression in human microvascular endothelial cells (HMEC-1). Of the three estrogens tested, ethinyl estradiol (EE), an estrogen receptor alpha (ERalpha) agonist, was the strongest inducer of RAGE expression in HMEC-1. By comparison, 17-epiestriol, an estrogen receptor beta (ERbeta) agonist and 17-beta-E2, an ER agonist that is almost equally potent for ERalpha and ERbeta were less effective in stimulating RAGE expression. We then determined whether the prooxidative and proinflammatory transcription factors Sp1 or NF-kappaB were downstream modulators of ER-agonists that mediate RAGE expression. The results implicated Sp1 but not NF-kappaB in estrogen-dependent RAGE expression. We further demonstrated that ERalpha but not ERbeta was responsible for the estrogen-mediated Sp1 activation. In summary, the present investigation demonstrates that a direct interaction of EE-ERalpha-Sp1 plays a central role in estrogen-induced RAGE expression in HMEC-1.
Mukherjee
Tapan K
TK
Pulmonary Division, Department of Internal Medicine, University of Utah Health Sciences Center, 30 North 1900 East, Room 4C104 SOM, Salt Lake City, UT 84132-4701, USA.
Reynolds
Paul R
PR
Hoidal
John R
JR
D015153:Blotting, Western; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004964:Estriol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists*; D047629:Estrogen Receptor beta / Q000819:agonists*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000378:metabolism
D017931:DNA Primers; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016329:Sp1 Transcription Factor; D004997:Ethinyl Estradiol; D004958:Estradiol; D004964:Estriol