Soluble receptor for advanced glycation end products RAGE (sRAGE), a secretory form of 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, complications of diabetes mellitus and atherosclerosis. Recent studies have suggested that fluid shear stress generated by laminar blood flow protects blood vessels from atherosclerosis, whereas low and oscillatory shear stress (OSS) generated by disturbed blood flow causes atherosclerosis. Although RAGE levels are increased in atherosclerotic plaque, the regulatory mechanisms of sRAGE in the occurrence of atherosclerotic plaque induced by disturbed blood flow remain largely unknown. This study aimed to determine the effects of sRAGE as a competitive inhibitor of RAGE in atherogenesis induced by disturbed blood flow. To determine the role of sRAGE in atherosclerosis induced by disturbed blood flow, we used a mouse model of partial carotid artery ligation using ApoE-/- and C57BL/6 mice. Our results revealed that the expression of RAGE was significantly increased in the region of atherosclerotic plaque and that treatment with sRAGE attenuated the development of plaque formation. We found that the expression levels of RAGE and high mobility group box 1 (HMGB1), the agonistic ligand of RAGE, were significantly increased in human umbilical vein endothelial cells (HUVECs) under shear stress conditions induced by disturbed blood flow and suppressed following treatment with sRAGE. We further observed that treatment with sRAGE decreased the expression of vascular cell adhesion molecule-1 (VCAM-1) and markedly attenuated monocyte-endothelial cell adhesion. Taken together, our results reveal that sRAGE exerts anti-atherogenic effects by blocking the activation of the RAGE signaling pathway induced by disturbed blood flow and may thus be a potential therapeutic target for the prevention of atherosclerosis.
- Endothelial cells
- Fluid shear stress
- Oscillatory shear stress
- Receptor of advanced glycation end products
- Soluble receptor of advanced glycation end products