Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1
Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1
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DOI：
10.1161/hypertensionaha.107.106963
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发表时间：
2008-06-01
期刊：
影响因子：
8.3
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Imayama, Ikuyo;Ichiki, Toshihiro;Sunagawa, Kenji
动脉粥样硬化被认为是一种脂质代谢和慢性炎症的复合疾病。最近的研究报道，肝X受体（LXR）参与脂质代谢和炎症，LXR激动剂抑制动脉粥样硬化形成。相反，众所周知，血管紧张素II通过激活血管紧张素II 1型受体（AT 1 R）加速动脉粥样硬化形成。为了更好地理解LXR预防动脉粥样硬化形成的机制，我们研究了LXR的激活是否影响血管平滑肌细胞中AT 1 R的表达。T0901317（一种合成LXR配体）可降低AT 1 R mRNA和蛋白表达，分别在孵育6小时和12小时达到峰值降低。LXR的一种公认的配体22-（R）-羟基胆固醇也抑制AT 1 R的表达。T0901317下调AT 1 R需要从头蛋白质合成。荧光素酶法检测AT 1 R基因启动子活性，发现-61 ~+25 bp的DNA片段足以下调AT 1 R基因启动子活性。在位于该区段的Sp1结合位点中具有突变的荧光素酶构建体失去了对T0901317的响应。T0901317降低Sp1丝氨酸磷酸化。虽然血管平滑肌细胞与T0901317预孵育30分钟对血管紧张素II诱导的细胞外信号调节激酶磷酸化没有影响，但血管紧张素II对细胞外信号调节激酶的磷酸化在预孵育6小时后显著抑制。这些结果表明，AT 1 R的抑制可能是LXR配体发挥抗动脉粥样硬化作用的重要机制之一。
Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between -61 bp and +25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II-induced extracellular signal-regulated kinase phosphorylation, phosphorylation of extracellular signal-regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects.