Integral role of receptor for advanced glycation end products (RAGE) in nondiabetic atherosclerosis

Hironori Uekita, Toshiyuki Ishibashi, Masashi Shiomi, Hidenori Koyama, Shukuko Ohtsuka, Hiroshi Yamamoto, Shoichi Yamagishi, Hiroyoshi Inoue, Hiroyuki Itabe, Koichi Sugimoto, Masashi Kamioka, Hiroshi Ohkawara, Ikuo Wada, Takeishi Yasuchika

Research output: Contribution to journalArticle

Abstract

An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a central role in the pathogenesis of diabetic vascular remodeling. This study was conducted to clarify the role of RAGE in nondiabetic atherosclerosis. We used the aortic and coronary atherosclerotic lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits prone to myocardial infarction (WHHLMI) at 1 to 14 months. Immunohistochemistry demonstrated the significant expression of RAGE as early as at 1 month with the stronger expression at 3 and 7 months, which was remarkably diminished at 14 months. RAGE expression was concordant with AGE accumulation. The major original sources of RAGE expression were macrophages and smooth muscle cells in addition to endothelial cells, and RAGE expression was distributed in the areas of phospholipid products, a component of oxidized LDL and nitrotyrosine. The concentrations of serum AGE did not alter significantly with aging. These findings suggested the expression of RAGE was induced by hyperlipidemia and oxidative stress independent of diabetes in WHHLMI rabbits. Additionally, our in vitro study showed that silencing of RAGE tended to attenuate oxidized-LDL-triggered PAI-1 expression in human cultured macrophages, as well as oxidized-LDL-induced tissue factor expression in peritoneal macrophages, suggesting a possible role of RAGE in prothrombogenic molecular regulation. In conclusion, the present study provides in vivo evidence that RAGE plays an integral role in the initiation and progression of nondiabetic atherosclerosis, suggesting that RAGE may be a novel target for treating not only diabetic but also nondiabetic vascular complications.

Original languageEnglish
Pages (from-to)109-121
Number of pages13
JournalFukushima journal of medical science
Volume65
Issue number3
DOIs
Publication statusPublished - 2019 Jan 1

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Keywords

  • Advanced glycation end products (AGE)
  • Atherosclerosis
  • Oxidized LDL
  • RAGE
  • WHHLMI rabbits

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Uekita, H., Ishibashi, T., Shiomi, M., Koyama, H., Ohtsuka, S., Yamamoto, H., Yamagishi, S., Inoue, H., Itabe, H., Sugimoto, K., Kamioka, M., Ohkawara, H., Wada, I., & Yasuchika, T. (2019). Integral role of receptor for advanced glycation end products (RAGE) in nondiabetic atherosclerosis. Fukushima journal of medical science, 65(3), 109-121. https://doi.org/10.5387/fms.2019-12