Journal
CIRCULATION RESEARCH
Volume 101, Issue 2, Pages 156-165Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.107.151746
Keywords
ABCA1; doxazosin; HDL; AP2; apoA-I
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ATP-binding cassette transporter A1 (ABCA1) is a rate-limiting factor for high-density lipoprotein ( HDL) biogenesis. The ABCA1 gene expression is known to be upregulated by various transcriptional factors. However, negative regulation factors would be better targets for pharmacological modulation of HDL biogenesis. Doxazosin, an alpha(1)-adrenoceptor blocker, increased ABCA1 mRNA, its protein, and apolipoprotein A-I-mediated HDL biogenesis in THP-1 macrophages and CHO-K1 cells, independent of alpha(1)-adrenoceptor blockade. Analysis of the human ABCA1 promoter indicated that the region between the positions -368 and -147 that contains an activator protein (AP)2-binding site responsible for the effects of doxazosin. Overexpression of AP2 alpha inhibited ABCA1 transcription in a dose-dependent fashion. Mutation in the AP2-binding site caused increase of the basal promoter activity and canceling both the transactivation by doxazosin and the trans-repression by AP2 alpha. Doxazosin had no effect on ABCA1 mRNA level in HepG2 cells, which lack endogenous AP2 alpha, and it reversed the inhibitory effect of AP2 alpha expression in this type of cells. Chromatin immunoprecipitation and gel shift assays revealed that doxazosin reduced specific binding of AP2 alpha to the ABCA1 promoter, as it suppressed phosphorylation of AP2 alpha. Finally, doxazosin increased ABCA1 expression and plasma HDL in mice. We thus concluded that AP2 alpha negatively regulates the ABCA1 gene transcription. Doxazosin inhibits AP2 alpha activity independent of alpha 1-adrenoceptor blockade and increases the ABCA1 expression and HDL biogenesis. AP2 alpha is a potent pharmacological target for the increase of HDL.
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