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

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32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)455-464
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume43
Issue number4
DOIs
Publication statusPublished - Oct 2007

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Ihara, Y., Egashira, K., Nakano, K., Ohtani, K., Kubo, M., Koga, J. I., Iwai, M., Horiuchi, M., Gang, Z., Yamagishi, S. I., & Sunagawa, K. (2007). Upregulation of the ligand-RAGE pathway via the angiotensin II type I receptor is essential in the pathogenesis of diabetic atherosclerosis. Journal of Molecular and Cellular Cardiology, 43(4), 455-464. https://doi.org/10.1016/j.yjmcc.2007.07.044