ATP-Binding Cassette Transporter A1 Gene Transcription Is Downregulated by Activator Protein 2α

• DOI: 10.1161/circresaha.107.151746
• Publication Date: 2007-06-08T01:11:22Z
• Authors: Noriyuki Iwamoto; Sumiko Abe-Dohmae; Makoto Ayaori; Nobukiyo Tanaka; Masatoshi Kusuhara; Fumitaka Ohsuzu; Shinji Yokoyama
• Keywords: Doxazosin; Chromatin immunoprecipitation

ATP-binding cassette transporter A1 (ABCA1) is a rate-limiting factor for high-density lipoprotein (HDL) biogenesis. The ABCA1 gene expression known to be upregulated by various transcriptional factors. However, negative regulation factors would better targets pharmacological modulation of HDL Doxazosin, an alpha(1)-adrenoceptor blocker, increased mRNA, its protein, and apolipoprotein A-I-mediated biogenesis in THP-1 macrophages CHO-K1 cells, independent blockade. Analysis the human promoter indicated that region between positions -368 -147 contains activator protein (AP)2-binding site responsible effects doxazosin. Overexpression AP2alpha inhibited transcription dose-dependent fashion. Mutation AP2-binding caused increase basal activity cancelling both transactivation doxazosin trans-repression AP2alpha. Doxazosin had no effect on mRNA level HepG2 which lack endogenous AP2alpha, it reversed inhibitory this type cells. Chromatin immunoprecipitation gel shift assays revealed reduced specific binding promoter, as suppressed phosphorylation Finally, plasma mice. We thus concluded negatively regulates transcription. inhibits blockade increases potent target HDL.