title: RAGE mediates accelerated diabetic vein graft atherosclerosis induced by combined mechanical stress and AGEs via synergistic ERK activation.
abstract: OBJECTIVE
  Diabetes with hypertension rapidly accelerates vascular disease, but the underlying mechanism remains unclear. We evaluated the hypothesis that the receptor of advanced glycation end products (RAGE) might mediate combined signals initiated by diabetes-related AGEs and hypertension-induced mechanical stress as a common molecular sensor.
  
  
  METHODS
  In vivo surgical vein grafts created by grafting vena cava segments from C57BL/6J mice into the common carotid arteries of streptozotocin (STZ)-treated and untreated isogenic mice for 4 and 8 weeks were analyzed using morphometric and immunohistochemical techniques. In vitro quiescent mouse vascular smooth muscle cells (VSMCs) with either knockdown or overexpression of RAGE were subjected to cyclic stretching with or without AGEs. Extracellular signal-regulated kinase (ERK) phosphorylation and Ki-67 expression were investigated.
  
  
  RESULTS
  Significant increases in neointimal formation, AGE deposition, Ki-67 expression, and RAGE were observed in the vein grafts of STZ-induced diabetic mice. The highest levels of ERK phosphorylation and Ki-67 expression in VSMCs were induced by simultaneous stretch stress and AGE exposure. The synergistic activation of ERKs and Ki-67 in VSMCs was significantly inhibited by siRNA-RAGE treatment and enhanced by over-expression of RAGE.
  
  
  CONCLUSIONS
  RAGE may mediate synergistically increased ERK activation and VSMC proliferation induced by mechanical stretching with and without AGEs. It may serve as a common molecular bridge between the two, accelerating vascular remodeling. This study provides potential drug targets and novel therapeutic strategies for the treatment of vascular diseases resulting from diabetes with hypertension.
authors.affiliation: Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuhuang
authors.initials: Y
authors.lastname: Li
authors.forename: Shuying
authors.initials: S
authors.lastname: Liu
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
authors.forename: Fukang
authors.initials: F
authors.lastname: Xie
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.forename: Suning
authors.initials: S
authors.lastname: Ping
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jintao
authors.initials: J
authors.lastname: Huang
authors.forename: Dadi
authors.initials: D
authors.lastname: Chen
authors.forename: Liping
authors.initials: L
authors.lastname: Hu
authors.forename: Chaohong
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology*; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000378:metabolism / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000502:physiology*; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000503:physiopathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology*; D013314:Stress, Mechanical; D017539:Tunica Intima / Q000254:growth & development / Q000378:metabolism; D014680:Veins / Q000378:metabolism / Q000637:transplantation*
chemical_list: D017127:Glycation End Products, Advanced; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D048049:Extracellular Signal-Regulated MAP Kinases