Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis

Yoshiko Ihara; Kensuke Egashira; Kaku Nakano; Kisho Ohtani; Mitsuki Kubo; Jun-ichiro Koga; Masaru Iwai; Masatsugu Horiuchi; Zhao Gang; Sho-ichi Yamagishi; Kenji Sunagawa

doi:10.1016/j.yjmcc.2007.07.044

Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis

J Mol Cell Cardiol. 2007 Oct;43(4):455-64. doi: 10.1016/j.yjmcc.2007.07.044. Epub 2007 Jul 21.

Authors

Yoshiko Ihara¹, Kensuke Egashira, Kaku Nakano, Kisho Ohtani, Mitsuki Kubo, Jun-ichiro Koga, Masaru Iwai, Masatsugu Horiuchi, Zhao Gang, Sho-ichi Yamagishi, Kenji Sunagawa

Affiliation

¹ Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

PMID: 17761193
DOI: 10.1016/j.yjmcc.2007.07.044

Abstract

The receptor for advanced glycation end products (RAGE) and the angiotensin II type I receptor (AT1R) have been separately linked to the pathogenesis of diabetic atherosclerosis. However, no prior study has addressed a linkage between RAGE and AT1R in diabetic atherogenesis. Therefore, we tested the hypothesis that upregulation of the ligand-RAGE axis via AT1R is an essential process underlying the disease. Diabetes was induced in apolipoprotein E-deficient (ApoE(-/-)) mice by streptozotocin, and diabetic mice were treated with AT1 receptor blocker (ARB) for 6 weeks. Diabetic ApoE(-/-) mice that were AT1R-deficient (ApoE(-/-)AT1aR(-/-)) were also investigated. In diabetic ApoE(-/-) mice, AT1R was found to increase within 1 week of diabetes induction, before ligand-RAGE pathway activation and other inflammatory changes were observed. Both ARB treatment and AT1aR deficiency suppressed diabetic atherosclerosis, ligand-RAGE expression and inflammatory changes. In contrast, upregulation of the ligand-RAGE pathway was noted in atherosclerotic plaques from non-diabetic ApoE(-/-) mice infused with angiotensin II. In cultured vascular smooth muscle cells, angiotensin II increased RAGE protein levels via AT1R stimulation. Upregulation of the ligand-RAGE pathway via AT1R is an essential mechanism in diabetic atherosclerosis, implying that ARB might decrease diabetic atherogenesis by inhibiting ligand-RAGE signals.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / physiology*
Angiotensin II Type 1 Receptor Blockers / pharmacology
Animals
Apolipoproteins E / genetics
Blood Pressure / drug effects
Cell Proliferation / drug effects
Cells, Cultured
Coronary Artery Disease / genetics*
Coronary Artery Disease / metabolism
Coronary Artery Disease / pathology
Coronary Artery Disease / physiopathology
Diabetes Mellitus, Experimental / genetics*
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Diabetes Mellitus, Experimental / physiopathology
Diabetic Angiopathies / genetics*
Diabetic Angiopathies / metabolism
Diabetic Angiopathies / pathology
Diabetic Angiopathies / physiopathology
Glycation End Products, Advanced / metabolism*
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / drug effects
Rats
Receptor for Advanced Glycation End Products
Receptors, Immunologic / genetics*
Renin-Angiotensin System / drug effects
Renin-Angiotensin System / physiology
Signal Transduction / genetics
Up-Regulation

Substances

Adaptor Proteins, Signal Transducing
Agtrap protein, mouse
Angiotensin II Type 1 Receptor Blockers
Apolipoproteins E
Glycation End Products, Advanced
Receptor for Advanced Glycation End Products
Receptors, Immunologic