A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor.
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 (PPARgamma) 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 PPARgamma-involved pathways but may involve a CD36-dependent mechanism.
Higashi
Yusuke
Y
Section of Cardiology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Peng
Tao
T
Du
Jie
J
Sukhanov
Sergiy
S
Li
Yangxin
Y
Itabe
Hiroyuki
H
Parthasarathy
Sampath
S
Delafontaine
Patrick
P
D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001011:Aorta / Q000166:cytology*; D017209:Apoptosis; D015153:Blotting, Western; D018955:CD36 Antigens / Q000096:biosynthesis / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D053938:DNA Fragmentation; D015536:Down-Regulation; D044950:Flavanones / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008084:Lipoxygenase / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000737:chemistry; D017382:Reactive Oxygen Species; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D018955:CD36 Antigens; D002839:Chromans; D044950:Flavanones; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; C006680:baicalein; D002374:Catalase; D008084:Lipoxygenase; D013482:Superoxide Dismutase; D017526:Receptor, IGF Type 1; D048051:p38 Mitogen-Activated Protein Kinases; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D010100:Oxygen