Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Ikenobe Miki-CHO, Kita-gun, Kagawa, Japan.
Horm Metab Res. 2010 Apr;42(4):241-6. doi: 10.1055/s-0029-1246183. Epub 2010 Jan 25.
Hyperglycemia is a major risk factor for atherosclerotic disease. The ATP-binding cassette transporter A1 (ABCA1) functions as a pivotal regulator of lipid efflux from cells to apolipoproteins and is thus involved in lowering the risk of atherosclerosis. In this study, we have examined the glucose-mediated regulation of the ABCA1 gene expression in vascular smooth muscle cells. ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and reporter gene assay. The results showed that the expression of the ABCA1 mRNA and protein decreased after the cells were treated with 22.4 mM glucose for 48 h. The transcriptional activity of the ABCA1 promoter paralleled the endogenous expression of the ABCA1 gene. Next, we used inhibitors of certain signal transduction pathways to demonstrate that the glucose-induced ABCA1 suppression is sensitive to the p38-mitogen-activated protein kinase (MAPK) inhibitors. The expression of a constitutively active form of p38-MAPK in the cells inhibited the ABCA1 promoter activity, irrespective of the presence of glucose. A dominant-negative mutant of p38-MAPK abrogated the inhibitory effect of glucose on the ABCA1 promoter activity. These results indicate that the glucose-induced suppression of ABCA1 expression is partially mediated by the activation of the p38-MAPK pathway.
高血糖是动脉粥样硬化疾病的一个主要危险因素。三磷酸腺苷结合盒转运体 A1（ABCA1）作为细胞内脂质向载脂蛋白转运的关键调节因子，从而参与降低动脉粥样硬化的风险。在这项研究中，我们研究了葡萄糖对血管平滑肌细胞中 ABCA1 基因表达的调节作用。通过实时聚合酶链反应（PCR）、Western blot 分析和报告基因检测来检测 ABCA1 的表达。结果表明，细胞用 22.4mM 葡萄糖处理 48 小时后，ABCA1mRNA 和蛋白的表达减少。ABCA1 启动子的转录活性与 ABCA1 基因的内源性表达平行。接下来，我们使用某些信号转导途径的抑制剂来证明葡萄糖诱导的 ABCA1 抑制对 p38-有丝分裂原激活蛋白激酶（MAPK）抑制剂敏感。细胞中 p38-MAPK 的组成型激活形式的表达抑制了 ABCA1 启动子活性，而与葡萄糖的存在与否无关。p38-MAPK 的显性失活突变体消除了葡萄糖对 ABCA1 启动子活性的抑制作用。这些结果表明，葡萄糖诱导的 ABCA1 表达抑制部分是由 p38-MAPK 通路的激活介导的。
