Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 29, Issue 11, Pages 1779-U139Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.109.191759
Keywords
glutathione; macrophage recruitment; metabolic stress; atherosclerosis; inflammation
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Funding
- National Institutes of Health [HL-70963]
- American Heart Association [0855011F]
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Background-Strengthening the macrophage glutathione redox buffer reduces macrophage content and decreases the severity of atherosclerotic lesions in LDL receptor-deficient (LDLR-/-) mice, but the underlying mechanisms were not clear. This study examined the effect of metabolic stress on the thiol redox state, chemotactic activity in vivo, and the recruitment of macrophages into atherosclerotic lesions and kidneys of LDL-R-/- mice in response to mild, moderate, and severe metabolic stress. Methods and Results-Reduced glutathione (GSH) and glutathione disulfide (GSSG) levels in peritoneal macrophages isolated from mildly, moderately, and severe metabolically-stressed LDL-R-/- mice were measured by HPLC, and the glutathione reduction potential (E-h) was calculated. Macrophage E-h correlated with the macrophage content in both atherosclerotic (r(2) = 0.346, P = 0.004) and renal lesions (r(2) = 0.480, P = 0.001) in these mice as well as the extent of both atherosclerosis (r(2) = 0.414, P = 0.001) and kidney injury (r(2) = 0.480, P = 0.001). Compared to LDL-R-/- mice exposed to mild metabolic stress, macrophage recruitment into MCP-1-loaded Matrigel plugs injected into LDL-R-/- mice increased 2.6-fold in moderately metabolically-stressed mice and 9.8-fold in severely metabolically-stressed mice. The macrophage Eh was a strong predictor of macrophage chemotaxis (r(2) = 0.554, P = 0.001). Conclusion-Thiol oxidative stress enhances macrophage recruitment into vascular and renal lesions by increasing the responsiveness of macrophages to chemoattractants. This novel mechanism contributes at least in part to accelerated atherosclerosis and kidney injury associated with dyslipidemia and diabetes in mice. (Arterioscler Thromb Vasc Biol. 2009; 29: 1779-1786.)
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