Do Atherosclerosis-associated Transcriptional Corepressors Interfere with Estrogen Signaling?

摘要

Controversy remains in regard to the use of hormone replacement therapy for the control of menopausal symptoms. Observational and clinical trials have highlighted the dichotomy of the effects of this therapy on the cardiovascular system. The data from a multitude of these studies indicate that once cardiovascular disease is present, hormone replacement therapy is detrimental. It is unclear why the addition of estrogen causes these negative effects. In foundational studies, we found that multiple transcriptional corepressors were upregulated in atherosclerotic vessels. We hypothesized that atherosclerosis-associated corepressors inhibit estrogen signaling by binding to the regulatory regions of estrogen-sensitive genes and preventing their transcription. A series of bioinformatics tools identified BATF as a possible corepressor which could inhibit estrogen-dependent signaling at AP-1 sites. Luciferase assays utilizing an AP-1-site luciferase reporter demonstrated that both BATF and ER&agr; have the ability to inhibit expression at this transcriptional regulatory site. We speculate that this unexpected action of ER&agr; at AP-1 sites may be due to the phosphorylation status of this receptor. Additional bioinformatics work with our foundational studies identified a novel pathway, MAPK1-dependent expression of the BAX gene via the transcription factor SP1, which may be involved in established atherosclerosis.