Class A scavenger receptor up-regulation in smooth muscle cells by oxidized low density lipoprotein
Class A scavenger receptor up-regulation in smooth muscle cells by oxidized low density lipoprotein
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DOI：
10.1074/jbc.275.23.17661
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发表时间：
2000-06-09
影响因子：
4.8
通讯作者：
Pitas, RE
中科院分区：
文献类型：
--
作者：
Mietus-Snyder, M;Gowri, MS;Pitas, RE
由磷酯或活性氧引起的氧化应激上调人体平滑肌细胞（SMC）中的A类清道夫受体（SR-A），而平滑肌细胞通常不表达该受体。SR-A表达的增加与氧化还原敏感转录因子激活蛋白1 c-Jun和CCAAT增强子结合蛋白β的激活有关。本研究表明，SMC与巨噬细胞或来自巨噬细胞条件培养基的氧化低密度脂蛋白（LDL）共孵育激活了这些游戏调节途径并刺激SR-A的表达。细胞氧化LDL诱导的SR-A基因转录增加上调SR-A mRNA，并使SR-A配体乙酰LDL的摄取增加30倍。铜氧化LDL也增加SR-A受体的表达。氧化LDL的过氧化脂质水平为80-100 nmol/mg，电泳迁移率为天然LDL的1.5倍，表现出最大的生物活性。抑制钙通量可抑制氧化LDL诱导SR-A。相反，钙离子载体通过氧化LDL或其他促进细胞内氧化应激的处理，大大增强了SR-A的上调。这种增强依赖于SMC环氧化酶-2表达和活性的同时上调，并被环氧化酶-2抑制剂NS-398和白藜芦醇阻断。在THP-I细胞中，氧化LDL诱导单核细胞向巨噬细胞分化并增加SR-A表达。这些发现支持了轻度氧化LDL在巨噬细胞分化和SR-A表达的氧化还原调节中的作用，并表明血管氧化应激的增加可能有助于SMC和巨噬细胞泡沫细胞的形成。
Oxidative stress caused by phorbol esters or reactive oxygen up-regulates the class A scavenger receptor (SR-A) in human smooth muscle cells (SMC), which normally do not express this receptor. The increase in SR-A expression correlates with activation of the redox-sensitive transcription factors activating protein-1 c-Jun and CCAAT enhancer-binding protein beta. Here we show that coincubation of SMC with macrophages or oxidized low density lipoproteins (LDL) from macrophage-conditioned medium activates these game regulatory pathways and stimulates SR-A expression. The increased SR-A gene transcription induced by cell-oxidized LDL up-regulated SR-A mRNA and increased by 30-fold the uptake of acetyl LDL, a ligand for the SR-A. Copper-oxidized LDL also increased SR-A receptor expression. Oxidized LDL with a lipid peroxide level of 80-100 nmol/mg of LDL protein and an electrophoretic mobility similar to 1.5 times that of native LDL exhibited the greatest bioactivity. Inhibition of calcium flux suppressed SR-A induction by oxidized LDL. Conversely, calcium ionophore greatly enhanced SR-A up-regulation by oxidized LDL or other treatments that promote intracellular oxidative stress. This enhancement was dependent upon concurrent up-regulation of SMC cyclooxygenase-2 expression and activity and was blocked by the cyclooxygenase-2 inhibitors NS-398 and Resveratrol. In THP-I cells, oxidized LDL induced monocyte-to-macrophage differentiation and increased SR-A expression. These findings support a role for mildly oxidized LDL in the redox regulation of macrophage differentiation and SR-A expression and suggest that increased vascular oxidative stress may contribute to the formation of both SMC and macrophage foam cells.