A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor
A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor
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DOI：
10.1194/jlr.m400478-jlr200
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发表时间：
2005-06-01
影响因子：
6.5
通讯作者：
Delafontaine, P
中科院分区：
文献类型：
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作者：
Higashi, Y;Peng, T;Delafontaine, P
氧化低密度脂蛋白（OxLDL）具有多种致动脉粥样硬化作用，包括诱导细胞凋亡。我们最近发现，OxLDL显着下调胰岛素样生长因子-1受体（IGF-1 R）在人主动脉平滑肌细胞，IGF-1 R过表达阻断OxLDL诱导的细胞凋亡。我们假设特定的OxLDL触发的信号传导事件导致IGF-1 R下调和细胞凋亡。我们研究了OxLDL信号通路，发现通过抑制OxLDL触发的细胞外信号调节激酶、p38丝裂原活化蛋白激酶（MAPK）或过氧化物酶体增殖物激活受体γ（PPAR γ）信号通路，既不能阻断IGF-1 R下调，也不能阻断促凋亡作用。然而，抗氧化剂，聚乙二醇过氧化氢酶，超氧化物歧化酶，和Trolox完全阻断IGF-1 R和OxLDL诱导的细胞凋亡的OxLDL下调。去甲二氢愈创木酸、AA-861和黄芩素是脂氧合酶抑制剂，也具有抗氧化活性，可阻断IGF-1 R下调和细胞凋亡以及活性氧（ROS）的产生。这些结果表明，氧化低密度脂蛋白可能通过脂氧合酶活性增强ROS的产生，导致IGF-1 R下调和细胞凋亡。此外，抗CD 36清道夫受体抗体显着抑制OxLDL诱导的IGF-1 R下调和细胞凋亡以及ROS的产生。总之，我们的数据表明，氧化低密度脂蛋白下调IGF-1 R通过氧化还原敏感的途径，这是不同的氧化低密度脂蛋白信号通过MAPK和过氧化物酶体增殖物激活受体γ参与的途径，但可能涉及CD 36依赖性机制。
Oxidized low density lipoprotein (OxLDL) has multiple proatherogenic effects, including induction of apoptosis. We have recently shown that OxLDL markedly downregulates insulin-like growth factor-1 receptor (IGF-1R) in human aortic smooth muscle cells, and that IGF-1R overexpression blocks OxLDL-induced apoptosis. We hypothesized that specific OxLDL-triggered signaling events led to IGF-1R downregulation and apoptosis. We examined OxLDL signaling pathways and found that neither IGF-1R downregulation nor the proapoptotic effect was blocked by inhibition of OxLDL-triggered extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), or peroxisome proliferator-activated receptor gamma ( PPAR gamma) signaling pathways, as assessed using specific inhibitors. However, antioxidants, polyethylene glycol catalase, superoxide dismutase, and Trolox completely blocked OxLDL downregulation of IGF-1R and OxLDL-induced apoptosis. Nordihydroguaiaretic acid, AA-861, and baicalein, which are lipoxygenase inhibitors and also have antioxidant activity, blocked IGF-1R downregulation and apoptosis as well as reactive oxygen species (ROS) production. These results suggest that OxLDL enhances ROS production possibly through lipoxygenase activity, leading to IGF-1R downregulation and apoptosis. Furthermore, anti-CD36 scavenger receptor antibody markedly inhibited OxLDL-induced IGF-1R downregulation and apoptosis as well as ROS production. In conclusion, our data demonstrate that OxLDL downregulates IGF-1R via redox-sensitive pathways that are distinct from OxLDL signaling through MAPK- and PPAR gamma-involved pathways but may involve a CD36-dependent mechanism.