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(Circulation Research. 2007;101:156.)
© 2007 American Heart Association, Inc.

Molecular Medicine

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

Doxazosin Inhibits Activator Protein 2 and Increases High-Density Lipoprotein Biogenesis Independent of ₁-Adrenoceptor Blockade

Noriyuki Iwamoto, Sumiko Abe-Dohmae, Makoto Ayaori, Nobukiyo Tanaka, Masatoshi Kusuhara, Fumitaka Ohsuzu, Shinji Yokoyama

From the Biochemistry Department (N.I., S.A.-D., N.T., S.Y.), Nagoya City University Graduate School of Medical Sciences; and the First Department of Internal Medicine (M.A., M.K., F.O.), National Defense Medical College, Tokorozawa, Japan.

Correspondence to Dr Shinji Yokoyama, Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan. E-mail syokoyam{at}med.nagoya-cu.ac.jp

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 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 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 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. Doxazosin had no effect on ABCA1 mRNA level in HepG2 cells, which lack endogenous AP2, and it reversed the inhibitory effect of AP2 expression in this type of cells. Chromatin immunoprecipitation and gel shift assays revealed that doxazosin reduced specific binding of AP2 to the ABCA1 promoter, as it suppressed phosphorylation of AP2. Finally, doxazosin increased ABCA1 expression and plasma HDL in mice. We thus concluded that AP2 negatively regulates the ABCA1 gene transcription. Doxazosin inhibits AP2 activity independent of ₁-adrenoceptor blockade and increases the ABCA1 expression and HDL biogenesis. AP2 is a potent pharmacological target for the increase of HDL.

Key Words: ABCA1 • doxazosin • HDL • AP2 • apoA-I

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