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Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 28, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp036
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice

Li Sun1,2, Tatsuro Ishida2, Tomoyuki Yasuda2, Yoko Kojima2, Tomoyuki Honjo2, Yasuhiko Yamamoto3, Hiroshi Yamamoto3, Shun Ishibashi4, Ken-ichi Hirata2 and Yoshitake Hayashi1

1 Division of Molecular Medicine & Medical Genetics, International Center for Medical Research and Treatment (ICMRT)
2 Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, 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

Address for correspondence: Tatsuro Ishida, MD, PhD. Division of Cardiovascular Medicine Kobe University Graduate School of Medicine 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Tel: +81-78-382-5846, Fax: +81-78-382-5859 E-mail: 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 hyperlipidemic 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 analyzed 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. Expressions of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the aorta were 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.

Conclusions: Oxidative LDL may be a ligand of RAGE in the hyperlipidemic state. RAGE inactivation inhibits the atherosclerosis through reducing oxLDL-induced pro-inflammatory responses and oxidative stress in hyperlipidemia.

Time for primary review: 33 Days


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