Thiol Oxidative Stress Induced by Metabolic Disorders Amplifies Macrophage Chemotactic Responses and Accelerates Atherogenesis and Kidney Injury in LDL Receptor-Deficient Mice

Abstract

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 (Eh) was calculated. Macrophage Eh correlated with the macrophage content in both atherosclerotic (r2=0.346, P=0.004) and renal lesions (r2=0.480, P=0.001) in these mice as well as the extent of both atherosclerosis (r2=0.414, P=0.001) and kidney injury (r2=0.480, P=...