Abstract 13852: Inhibitory Effect of Soluble RAGE in Disturbed Flow Induced Atherogenesis
Soluble RAGE (sRAGE), an endogenous secretory receptor form of receptor for advanced glycation end products (RAGE), plays an important role in suppressing RAGE signals that induce pro-inflammatory gene activation in a range of inflammatory diseases such as Alzheimer's disease, diabetic complications, and atherosclerosis. Recent studies have suggested that fluid shear stress generated through laminar blood flow protects blood vessels from atherosclerosis but disturbed shear stress in blood vessels may cause atherosclerosis. However, the regulatory mechanisms of sRAGE for occurrence of atherosclerotic plaques Induced by disturbed flow remain largely unknown. The study was designed to demonstrate the protecting role of sRAGE as a competent inhibitor of RAGE in atherogenesis and its cellular signaling pathways underlying disturbed flow induction of various agonistic ligands such as advanced glycation end products (AGEs) and high mobility group protein B1 (HMGB1).To analyze the role of sRAGE in atherosclerosis induced by disturbed flow, we used partial carotid ligation model in ApoE-/- and C57/BL6 mice. These animal models had impaired steady laminar blood flow and exhibited marked atherosclerotic plaques. Here we showed that the expression of RAGE was significantly increased in the region of atherosclerotic plaque and treatment of sRAGE (2 μg per mouse) attenuates the development of plaque formation (30%). Also, we found that the expression level of HMGB1, S100A12, S100B, the agonistic ligands of RAGE, were hugely increased in the disturbed shear stress (± 5 dyne / cm2) in endothelial cells. We further observed that treatment of sRAGE (8 μg / mL) decreased the expression of adhesion receptor molecules such as ICAM-1 and VCAM-1 and importantly attenuated the flow-inhibitory effect on monocyte adhesion to endothelial cells. Taken together, our results reveal that sRAGE has anti-inflammatory effects through blocking RAGE-induced signaling pathway in disturbed flow and may be as a potential therapeutic target for the prevention of atherosclerosis.
- © 2012 by American Heart Association, Inc.