Oxidized low-density lipoprotein accelerates the destabilization of extracellular-superoxide dismutase mRNA during foam cell formation
Oxidized low-density lipoprotein accelerates the destabilization of extracellular-superoxide dismutase mRNA during foam cell formation
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氧化低密度脂蛋白在泡沫细胞形成过程中加速细胞外超氧化物歧化酶 mRNA 的不稳定
DOI：
10.1016/j.abb.2015.04.001
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Adachi T
中科院分区：
文献类型：
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作者：
Makino J;Nii M;Kamiya T;Hara H;Adachi T
细胞外超氧化物歧化酶(EC-SOD)是保护细胞免受超氧化物损伤的主要抗氧化酶之一。在本研究中，我们研究了氧化型低密度脂蛋白(OxLDL)诱导THP-1来源的巨噬细胞泡沫细胞形成过程中EC-SOD表达的调节。OxLDL呈时间依赖性地增加THP-1来源的巨噬细胞对oxLDL的摄取，降低EC-SOD的表达。此外，通过与清道夫受体，尤其是CD36的结合，oxLDL对EC-SOD的抑制是通过与siRNA经验的结果相联系而实现的。在人类细胞系中，EC-SOD的表达受组蛋白乙酰化和转录因子Sp1/3与EC-SOD启动子区域结合的调节。然而，oxLDL并不影响这些过程。另一方面，oxLDL降低了EC-SOD mRNA的稳定性。此外，ox低密度脂蛋白促进EC-SOD或嵌合的铜锌超氧化物歧化酶基因异位表达的mRNA失稳，而oxLDL对缺失该序列的EC-SOD基因异位表达的mRNA没有影响。这些结果表明，oxLDL降低EC-SOD的表达，进而加速EC-SOD mRNA的失稳，导致对氧化应激和动脉粥样硬化的保护作用减弱。
Extracellular-superoxide dismutase (EC-SOD) is one of the main anti-oxidative enzymes that protect cells against the damaging effects of superoxide. In the present study, we investigated the regulation of EC-SOD expression during the oxidized low density lipoprotein (oxLDL)-induced foam cell formation of THP-1-derived macrophages. The uptake of oxLDL into THP-1-derived macrophages was increased and EC-SOD expression was decreased in a time-dependent manner by oxLDL. Furthermore, EC-SOD suppression by oxLDL was mediated by the binding to scavenger receptors, especially CD36, from the results with siRNA experience. EC-SOD expression is known to be regulated by histone acetylation and binding of the transcription factor Sp1/3 to the EC-SOD promoter region in human cell lines. However, oxLDL did not affect these processes. On the other hand, the stability of EC-SOD mRNA was decreased by oxLDL. Moreover, oxLDL promoted destabilization of ectopically expressed mRNA from EC-SOD or chimeric Cu,Zn-SOD gene with the sequence corresponding to 3′UTR of EC-SOD mRNA, whereas oxLDL had no effect on ectopic mRNA produced from EC-SOD gene lacking the sequence. These results suggested that oxLDL decreased the expression of EC-SOD, which, in turn, accelerated the destabilization of EC-SOD mRNA, leading to weaker protection against oxidative stress and atherosclerosis.