Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products

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Abstract

Background: Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products)-MAPK signalling pathway may play an important pathogenetic role. As recently S 100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of Sl00A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression. Methods: Human umbilical vein endothelial cells (HUVEC) were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9. Results: Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCPI in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK 1/2 and p38 by PD 98059 and SB 203580, respectively. Conclusion: The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiologica entities associated with a high AGE burden. Thus, blocking heterodimeric Sl00A8/Sl00A9 might represent a novel therapeutic modality in treating atherosclerosis. © 2006 Ehlermann et al; licensee BioMed Central Ltd.

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Ehlermann, P., Eggers, K., Bierhaus, A., Most, P., Weichenhan, D., Greten, J., … Remppis, A. (2006). Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products. Cardiovascular Diabetology, 5. https://doi.org/10.1186/1475-2840-5-6

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