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Papers In Press, published online ahead of print June 1, 2005
J. Lipid Res., doi:10.1194/jlr.M400478-JLR200

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Journal of Lipid Research, Vol. 46, 1266-1277, June 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor

Yusuke Higashi^*, Tao Peng, Jie Du, Sergiy Sukhanov^*, Yangxin Li^*, Hiroyuki Itabe, Sampath Parthasarathy^** and Patrick Delafontaine^1,*

^* Section of Cardiology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112
Division of Nephrology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555
Department of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan
^** Department of Pathology, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112

The online version of this article (available at http://www.jlr.org) contains an additional figure.

Published, JLR Papers in Press, April 1, 2005. DOI 10.1194/jlr.M400478-JLR200

¹ To whom correspondence should be addressed. e-mail: pdelafon{at}tulane.edu

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 (PPAR) 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-involved pathways but may involve a 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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