出版社：American Society for Biochemistry and Molecular Biology
摘要：Oxidized low density lipoprotein (OxLDL) has multiple proatherogeniceffects, including induction of apoptosis. We have recentlyshown that OxLDL markedly downregulates insulin-like growthfactor-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 eventsled to IGF-1R downregulation and apoptosis. We examined OxLDLsignaling pathways and found that neither IGF-1R downregulationnor the proapoptotic effect was blocked by inhibition of OxLDL-triggeredextracellular signal-regulated kinase, p38 mitogen-activatedprotein kinase (MAPK), or peroxisome proliferator-activatedreceptor (PPAR) signaling pathways, as assessed using specificinhibitors. However, antioxidants, polyethylene glycol catalase,superoxide dismutase, and Trolox completely blocked OxLDL downregulationof IGF-1R and OxLDL-induced apoptosis. Nordihydroguaiareticacid, AA-861, and baicalein, which are lipoxygenase inhibitorsand also have antioxidant activity, blocked IGF-1R downregulationand apoptosis as well as reactive oxygen species (ROS) production.These results suggest that OxLDL enhances ROS production possiblythrough lipoxygenase activity, leading to IGF-1R downregulationand apoptosis. Furthermore, anti-CD36 scavenger receptor antibodymarkedly inhibited OxLDL-induced IGF-1R downregulation and apoptosisas well as ROS production.
In conclusion, our data demonstrate that OxLDL downregulatesIGF-1R via redox-sensitive pathways that are distinct from OxLDLsignaling through MAPK- and PPAR-involved pathways but may involvea CD36-dependent mechanism.Abbreviations: ERK, extracellular signal-regulated kinase; HASMC, human aortic smooth muscle cell; 13-HODE, 13-(S)-hydroxyoctadecadienoic acid; 13-HPODE, 13-hydroperoxyoctadecadienoic acid; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; MAPK, mitogen-activated protein kinase; NDGA, nordihydroguaiaretic acid; nLDL, native low density lipoprotein; OxLDL, oxidized low density lipoprotein; PEG, polyethylene glycol; PPAR, peroxisome proliferator-activated receptor ; ROS, reactive oxygen species; SMC, smooth muscle cell; SOD, superoxide dismutase; SR-A, scavenger receptor class A; TBARS, thiobarbituric acid-reactive substances
Supplementary key words reactive oxygen species • oxidized low density lipoprotein • atherosclerosis
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