Cardiovascular Research Advance Access first published online on January 28, 2009
This version [Corrected Proof] published online on February 18, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp036
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RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice
1 Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment (ICMRT), Kobe University Graduate School of Medicine, Kobe, Japan
2 Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
3 Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
4 Division of Endocrinology and Metabolism, Jichi Medical School, Tochigi, Japan
* Corresponding author. Tel: +81 78 382 5846; fax: +81 78 382 5859. E-mail address: ishida{at}med.kobe-u.ac.jp
Aims: Receptor for advanced glycation end products (RAGE) plays a pivotal role in the genesis of diabetic vascular diseases. To further explore the mechanisms underlying atherosclerosis under non-diabetic conditions, we examined the effect of RAGE deficiency on atherosclerosis in hyperlipidaemic mice.
Methods and results: RAGE–/– mice were crossed with low-density lipoprotein receptor-deficient (LDLr–/–) mice to generate the double knockout (DKO) mice. After feeding with high-fat diet for 12 weeks, aortic atherosclerotic lesions were analysed histologically in these mice. Although there were no differences in serum levels of glucose and known RAGE ligands between DKO and LDLr–/– mice, DKO mice exhibited a significant decrease in the size and macrophage content in atherosclerotic lesions compared with LDLr–/– mice. Expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the aorta was lower in DKO mice than in LDLr–/– mice. Fluorescence-based assays revealed that oxidative stress in the vessel wall was attenuated in DKO mice than in LDLr–/– mice. Cell culture experiments revealed that RAGE mediated oxidative LDL-induced activation of p42/44 mitogen-activated protein kinases and oxidative stress in macrophages.
Conclusion: Oxidative LDL may be a ligand of RAGE in the hyperlipidaemic state. RAGE inactivation inhibits the atherosclerosis through reducing oxLDL-induced pro-inflammatory responses and oxidative stress in hyperlipidaemia.
KEYWORDS Atherosclerosis; Adhesion molecule; Oxidized LDL; Oxidative stress; RAGE
Time for primary review: 33 days