title: AGEs-RAGE system mediates atrial structural remodeling in the diabetic rat.
abstract: BACKGROUND
  Diabetes mellitus (DM) is one of the independent risk factors for atrial fibrillation (AF). Our previous study has indicated that DM causes atrial structural remodeling with intraatrial conduction disturbances. We tested the hypothesis that the advanced glycation end products (AGEs) and the receptor for AGE (RAGE), which have been implicated in diabetic complications, are responsible for the atrial structural remodeling.
  
  
  RESULTS
  Diabetes was induced by streptozotocin (65 mg/kg i.p.) in 8-week-old female Sprague-Dawley rats. When 24 weeks old, their atria were subjected to histology, Western blotting, and immunohistochemistry. The HbA(1c) value of induced-DM rats was significantly higher than that of control rats. Histological and immunohistochemical examinations revealed that the atria of diabetic rats showed remarkable structural changes characterized by diffuse interstitial fibrosis with abundant expressions of RAGE and connective tissue growth factor (CTGF), which findings were also confirmed by Western blotting analysis. This diabetes-induced atrial fibrosis was remarkably prevented by administration of an inhibitor of AGEs formation, OPB-9195, along with reduction of CTGF expression.
  
  
  CONCLUSIONS
  DM promoted atrial structural remodeling via the activation of the AGEs-RAGE system with upregulating CTGF. The inhibition of AGEs formation could be a novel upstream therapeutic approach for diabetes-related atrial fibrosis.
authors.affiliation: The Cardiovascular Institute, Tokyo, Japan. takeshikato@mac.com
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Akiko
authors.initials: A
authors.lastname: Sekiguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsuneda
authors.forename: Kouichi
authors.initials: K
authors.lastname: Sagara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takamura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Tadanori
authors.initials: T
authors.lastname: Aizawa
authors.forename: Long-Tai
authors.initials: LT
authors.lastname: Fu
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013311:Streptozocin