Receptor for AGE (RAGE) mediates neointimal formation in response to arterial injury.
BACKGROUND
Receptor for advanced-glycation end products (RAGE) and its ligands AGEs and S100/calgranulins have been implicated in a range of disorders. However, the role of RAGE/ligand interaction in neointimal hyperplasia after vascular injury remains unclear.


RESULTS
We examined the expression of RAGE and its ligands after balloon injury of the carotid artery in both Zucker diabetic and nondiabetic rats. Using a soluble portion of the extracellular domain of RAGE, we determined the effects of suppressing RAGE/ligand interaction on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. We demonstrate a significantly increased accumulation of AGE and immunoreactivities of RAGE and S100/calgranulins in response to balloon injury in diabetic compared with nondiabetic rats. Blockade of RAGE/ligand interaction significantly decreased S100-stimulated VSMC proliferation in vitro and bromodeoxyuridine (BrdU)-labeled proliferating VSMC in vivo, and suppressed neointimal formation and increased luminal area in both Zucker diabetic and nondiabetic rats.


CONCLUSIONS
These findings indicate that RAGE/ligand interaction plays a key role in neointimal formation after vascular injury irrespective of diabetes status and suggest a novel target to minimize neointimal hyperplasia.
Experimental Interventional Laboratory, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Zhongmin
Z
Zhou
Kai
K
Wang
Marc S
MS
Penn
Steven P
SP
Marso
Michael A
MA
Lauer
Farhad
F
Forudi
Xiaorong
X
Zhou
Wu
W
Qu
Yan
Y
Lu
David M
DM
Stern
Ann Marie
AM
Schmidt
A Michael
AM
Lincoff
Eric J
EJ
Topol
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000209:etiology* / Q000473:pathology; D001786:Blood Glucose / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000276:immunology; D007150:Immunohistochemistry; D007700:Kinetics; D039841:Leukocyte L1 Antigen Complex / Q000032:analysis / Q000276:immunology; D008024:Ligands; D008055:Lipids / Q000097:blood; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis / Q000276:immunology / Q000502:physiology*
D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D039841:Leukocyte L1 Antigen Complex; D008024:Ligands; D008055:Lipids; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic