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Shear stress modulates RAGE-mediated inflammation in a model of diabetes-induced metabolic stress

, : Shear stress modulates RAGE-mediated inflammation in a model of diabetes-induced metabolic stress. American Journal of Physiology. Heart and Circulatory Physiology 302(12): H2498-H2508

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/cm2), which downregulated RAGE by fourfold, or oscillatory SS (OSS; ± 5 dyn/cm2), 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 (.5 ng/ml) and the RAGE ligand high mobility group box 1 (HMGB1). A 5% increase in VCAM-1 expression over TNF-α was associated with increased cytoplasmic and mitochondrial reactive oxygen species and NF-B 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.


PMID: 22467309

DOI: 10.1152/ajpheart.00869.2011

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