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. 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.