S100A8 and S100A9 Mediate Endotoxin-Induced Cardiomyocyte Dysfunction via the Receptor for Advanced Glycation End Products

• DOI: 10.1161/circresaha.107.167544
• Publication Date: 2008-04-11T01:54:35Z
• Authors: John H. Boyd; Bernard Kan; Haley Roberts; Yingjin Wang; Keith R. Walley
• Keywords: S100A9; S100A8; Contractility; Proinflammatory cytokine; RAGE

Cardiovascular dysfunction as a result of sepsis is the leading cause death in critically ill. Cardiomyocytes respond to infectious pathogens with Toll-like receptor–initiated proinflammatory response conjunction decrease contractility, although downstream events linking receptor activation and reduced cardiac contractility remain be elucidated. Using microarray analysis tissue exposed systemic lipopolysaccharide (LPS), we discovered that 2 small calcium-regulating proteins (S100A8 S100A9) are highly upregulated. HL-1 cardiomyocytes, isolated primary live mice were LPS, whereas beating cells had S100A8 S100A9 overexpressed their calcium flux quantified. vivo microbubble technology, delivered normal mouse hearts; using same inhibited production hearts subsequently them LPS. Coimmunoprecipitation identified interaction RAGE (the for advanced glycation end products), function postreceptor signaling which investigated. whole LPS have large increases S100A9. Cardiac overexpression led RAGE-dependent and, intact mouse, decreased ejection fraction, knockdown attenuated LPS-induced dysfunction. express S100A9, RAGE-mediated cardiomyocyte contractility. This finding provides novel mechanistic link between circulating pathogen-associated molecular products subsequent