title: Shear stress modulates RAGE-mediated inflammation in a model of diabetes-induced metabolic stress.
abstract: Atherosclerosis occurs preferentially at sites of disturbed blood flow despite the influence of risk factors contributing to systemic inflammation. The receptor for advanced glycation endproducts (RAGE) is a prominent mediator of inflammation in diabetes that is upregulated in atherosclerotic plaques. Our goal was to elucidate a role for arterial hemodynamics in the regulation of RAGE expression and activity. Endothelial RAGE expression was elevated at sites of flow disturbance in the aortas of healthy swine. To demonstrate a direct role for physiological shear stress (SS) in modulating RAGE expression, human aortic endothelial cells (HAEC) were exposed to high SS (HSS; 15 dyn/cm(2)), which downregulated RAGE by fourfold, or oscillatory SS (OSS; 0 ± 5 dyn/cm(2)), which upregulated RAGE by threefold, compared with static culture at 4 h. In a model of diabetes-induced metabolic stress, HAEC were chronically conditioned under high glucose (25 mM) and then simultaneously stimulated with TNF-α (0.5 ng/ml) and the RAGE ligand high mobility group box 1 (HMGB1). A 50% increase in VCAM-1 expression over TNF-α was associated with increased cytoplasmic and mitochondrial reactive oxygen species and NF-κB activity. This increase was RAGE-specific and NADPH oxidase dependent. In activated HAEC, OSS amplified HMGB1-induced VCAM-1 (3-fold) and RAGE (1.6-fold) expression and proportionally enhanced monocyte adhesion to HAEC in a RAGE-dependent manner, while HSS mitigated these increases to the level of TNF-α alone. We demonstrate that SS plays a fundamental role in regulating RAGE expression and inflammatory responses in the endothelium. These findings may provide mechanistic insight into how diabetes accelerates the nonrandom distribution of atherosclerosis in arteries.
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, California 95616, USA.
authors.forename: J Sherrod
authors.initials: JS
authors.lastname: DeVerse
authors.forename: Keith A
authors.initials: KA
authors.lastname: Bailey
authors.forename: Kaleena N
authors.initials: KN
authors.lastname: Jackson
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Passerini
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D013314:Stress, Mechanical; D013312:Stress, Physiological / Q000502:physiology*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1