Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) transcriptional regulation by Oct-1 in human endothelial cells: implications for atherosclerosis
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DOI：
10.1042/bj20050845
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发表时间：
2006-01-01
影响因子：
4.1
通讯作者：
Mehta, JL
中科院分区：
文献类型：
--
作者：
Chen, JW;Liu, Y;Mehta, JL
LOX-1是ox-LDL（氧化低密度脂蛋白）的受体，最近已被确定在动脉粥样硬化的进展中起关键作用。LOX-1的表达（mRNA和蛋白质）已被证明是上调的促动脉粥样硬化的刺激，如ox-LDL和血管紧张素II（血管紧张素II）。然而，这些上调的分子机制尚不清楚。在本研究中，我们探讨LOX-1转录启动子激活响应ox-LDL和Ang II。在基础状态下，发现L0 X-1核心启动子（L0 X-1 - 35/+36）足以在HCAEC（人冠状动脉内皮细胞）中发挥其基础活性。更重要的是，我们发现ox-LDL（60 μ g/ml，24小时）显著诱导LOX-1启动子活性，并且这种激活需要105 bp片段（nt-1599和-1494之间）。在这个106 bp的片段内，存在转录因子Oct-1（八聚体-1）的潜在结合基序。电泳迁移率改变法观察ox-LDL对Oct-1的激活作用。突变试验进一步证实Oct-1在ox-LDL诱导的LOX-1启动子激活中的关键作用。为了进行比较，我们还检测了LOX-1启动子对Ang II（1 μ mol/l，24 h）的激活。有趣的是，另一个启动子区域，nt - 2336和-1990之间，所需的血管紧张素II诱导的LOX-1启动子激活。总之，本研究强烈表明，ox-LDL，通过激活Oct-1诱导LOX-1启动子激活。此外，这项研究表明，虽然ox-LDL和Ang II都诱导LOX-1在HCAEC中的表达，启动子激活的潜在机制是彼此不同的。
LOX-1 a receptor for ox-LDL (oxidized low-density lipoprotein), has recently been determined to play a critical role in the progression of atherosclerosis. LOX-1 expression (mRNA and protein) has been shown to be up-regulated by pro-atherogenic stimuli, such as ox-LDL and Ang II (angiotensin II). However, the molecular mechanisms of these up-regulations are unclear. In the present study, we explored LOX-1 transcriptional promoter activation in response to ox-LDL and Ang II. Under basal states, LOX-1 core promoter (LOX-1 -35/+36) was found to be sufficient for its basal activity in HCAECs (human coronary artery endothelial cells). More importantly, we found that ox-LDL (60 mu g/ml for 24 h) induced LOX-1 promoter activity significantly and that a 105 bp fragment (between nt -1599 and -1494) was required for this activation. Within this 106 bp fragment, there is a potential binding motif for the transcription factor Oct-1 (octamer-1). By electrophoretic mobility-shift assay, we observed the activation of Oct-1 by ox-LDL. The critical role of Oct-1 in ox-LDL-induced LOX-1 promoter activation was further confirmed by mutagenesis assay. For comparison, we also examined LOX-1 promoter activation in response to Ang II (1 mu mol/l for 24 h). Interestingly, another promoter region, between nt - 2336 and - 1990, was required for Ang II-induced LOX-1 promoter activation. In conclusion, the present study strongly suggests that ox-LDL, by activating Oct-1 induces LOX-1 promoter activation. Furthermore, this study suggests that while ox-LDL and Ang II both induce LOX-1 expression in HCAECs, the underlying mechanisms of promoter activation are different from each other.