Abstract
Aim: The receptor for advanced glycation end-products (RAGE) has been suggested to play a pivotal role in the development of diabetic vasculopathy and atherosclerosis; however, due to its low expression, the physiological role of RAGE in vascular smooth muscle cells (VSMC) remains unknown.
Methods: Using VSMC lines stably expressing RAGE (RAGE-A10), we studied the molecular mechanism by which S100B, a RAGE ligand, induces proinflammatory gene expression.
Results: S100B induced NF-κB activation and the expression of several proinflammatory genes (MCP-1, IL-6, ICAM-1) at mRNA and protein levels in RAGE-A10, among which MCP-1 expression was the most robust. S100B-induced MCP-1 expression was dose-dependently blocked by inhibitors of JNK (SP600125), p38 (SB203580), MEK-1 (U0126) as well as NF-κB (Bay117085). In RAGE-A10, S100B activated JNK, MEK-1 and p38. S100B-induced MCP-1 promoter activity via NF-κB binding sites and nuclear translocation of NF-κB p65 subunit were blocked by SP600125, U0126, and SB203580 in RAGE-A10.
Conclusion: Our study demonstrates that S100B increased MCP-1 expression via NF-κB and mitogen-activated protein kinase (JNK, ERK1/2, and p38) pathways in RAGE-overexpressed A10 cell lines. Thus, RAGE-A10 could be a useful cell model for studying the molecular mechanism(s) of up-regulated RAGE in the vasculature.
