Published online before print April 28, 2003, doi: 10.1161/01.CIR.0000063577.32819.23
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(Circulation. 2003;107:2238.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Receptor for AGE (RAGE) Mediates Neointimal Formation in Response to Arterial Injury
From the Experimental Interventional Laboratory, Department of Cardiovascular Medicine (Z.Z., K.W., M.S.P., F.F., X.Z., A.M.L., E.J.T.), Cleveland Clinic Foundation, Cleveland, Ohio; Mid American Heart Institute (S.P.M.), Saint Luke’s Hospital, Kansas City, Mo; Borgess Hospital Research Institute (M.A.L.), Kalamazoo, Mich; and Columbia University (W.Q., Y.L., A.M.S., D.M.S.), College of Physician and Surgeons, New York, NY.
Correspondence to Eric J. Topol, MD, Dept of Cardiovascular Medicine F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail topole{at}ccf.org
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.
Methods and 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.
Key Words: diabetes mellitus • angioplasty • restenosis • receptors
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