ATP-binding cassette transporter A1 gene transcription is downregulated by activator protein 2alpha. Doxazosin inhibits activator protein 2alpha and increases high-density lipoprotein biogenesis independent of alpha1-adrenoceptor blockade.
ATP-binding cassette transporter A1 gene transcription is downregulated by activator protein 2alpha. Doxazosin inhibits activator protein 2alpha and increases high-density lipoprotein biogenesis independent of alpha1-adrenoceptor blockade.
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发表时间：
2007
影响因子：
20.1
通讯作者：
N. Iwamoto;S. Abe-Dohmae;M. Ayaori;Nobukiyo Tanaka;M. Kusuhara;F. Ohsuzu;S. Yokoyama
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文献类型：
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作者：
N. Iwamoto;S. Abe-Dohmae;M. Ayaori;Nobukiyo Tanaka;M. Kusuhara;F. Ohsuzu;S. Yokoyama
atp结合盒转运蛋白A1 （ABCA1）是高密度脂蛋白（HDL）生物生成的限速因子。ABCA1基因的表达被各种转录因子上调。然而，负调节因子可能是HDL生物发生的更好的药理调节靶点。Doxazosin是一种α(1)-肾上腺素受体阻滞剂，可增加THP-1巨噬细胞和CHO-K1细胞中ABCA1 mRNA、其蛋白和载脂蛋白a - i介导的HDL生物生成，不依赖于α(1)-肾上腺素受体阻断。对人ABCA1启动子的分析表明，位于-368和-147之间的区域含有一个激活蛋白（AP）2结合位点，负责doxazosin的作用。AP2alpha的过表达以剂量依赖性方式抑制ABCA1的转录。ap2结合位点的突变导致基础启动子活性增加，取消了doxazosin的反式激活和AP2alpha的反式抑制。Doxazosin对缺乏内源性AP2alpha的HepG2细胞中ABCA1 mRNA水平无影响，逆转了AP2alpha表达的抑制作用。染色质免疫沉淀和凝胶移位实验显示，doxazosin抑制AP2alpha的磷酸化，从而降低了AP2alpha与ABCA1启动子的特异性结合。最后，doxazosin增加小鼠ABCA1表达和血浆HDL。我们由此得出结论，AP2alpha负调控ABCA1基因的转录。Doxazosin抑制独立于α(1)-肾上腺素能受体阻断的AP2alpha活性，增加ABCA1表达和HDL的生物发生。AP2alpha是增加HDL的有效药理学靶点。
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 AP2alpha inhibited ABCA1 transcription in a dose-dependent fashion. Mutation in the AP2-binding site caused increase of the basal promoter activity and cancelling both the transactivation by doxazosin and the trans-repression by AP2alpha. Doxazosin had no effect on ABCA1 mRNA level in HepG2 cells, which lack endogenous AP2alpha, and it reversed the inhibitory effect of AP2alpha expression in this type of cells. Chromatin immunoprecipitation and gel shift assays revealed that doxazosin reduced specific binding of AP2alpha to the ABCA1 promoter, as it suppressed phosphorylation of AP2alpha. Finally, doxazosin increased ABCA1 expression and plasma HDL in mice. We thus concluded that AP2alpha negatively regulates the ABCA1 gene transcription. Doxazosin inhibits AP2alpha activity independent of alpha(1)-adrenoceptor blockade and increases the ABCA1 expression and HDL biogenesis. AP2alpha is a potent pharmacological target for the increase of HDL.