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

Content Provider	Europe PMC
Author	Uekita, Hironori Ishibashi, Toshiyuki Shiomi, Masashi Koyama, Hidenori Ohtsuka, Shukuko Yamamoto, Hiroshi Yamagishi, Shoichi Inoue, Hiroyoshi Itabe, Hiroyuki Sugimoto, Koichi Kamioka, Masashi Ohkawara, Hiroshi Wada, Ikuo Takeishi, Yasuchika
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.
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ISSN	00162590
Volume Number	65
DOI	10.5387/fms.2019-12
PubMed Central reference number	PMC7012590
Issue Number	3
PubMed reference number	31915324
Journal	Fukushima Journal of Medical Science [Fukushima J Med Sci]
e-ISSN	21854610
Language	English
Publisher	The Fukushima Society of Medical Science
Publisher Date	2019-01-01
Access Restriction	Open
Subject Keyword	Advanced glycation end products (AGE) RAGE Atherosclerosis WHHLMI rabbits Oxidized LDL
Content Type	Text
Resource Type	Article
Subject	Medicine