Abstract 203: Redox Regulation of MKP-1 and the Functional Reprogramming of Monocyte-Derived Macrophages by Metabolic Stress

Abstract

Objective: To determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Methods and Results: Transplantation of MKP-1-deficient (MKP KO ) bone marrow into LDL-R -/- (MKP-1 LeuKO ) mice accelerated high fat diet (HFD)-induced atherosclerotic lesion formation. After 12 weeks of HFD feeding, MKP-1 LeuKO mice showed increases in lesion size in both the aortic root and the aorta, despite reduced plasma cholesterol levels. Macrophage content was increased in lesions of MKP-1 LeuKO mice compared to mice that received wt bone marrow. After only 6 weeks on a HFD, the in vivo chemotactic activity of monocytes was already significantly increased in MKP-1 LeuKO mice. Macrophages isolated from MKP KO mice showed impaired autophagy, increased sensitivity to 7-ketocholesterol-induced apoptosis, and IL-4-induced M2 polarization of these macrophages was blocked. Importantly, macrophages in atherosclerotic lesion of MKP-1 LeuKO mice showed increased macrophage apoptosis and decreased autophagy. Metabolic stress in vitro mimicked the functional phenotype of MKP-1 deficiency, and overexpression of MKP-1 protected macrophages from metabolic stress-induced dysfunction and reprogramming. Conclusions: Loss of MKP-1 activity promotes monocyte dysfucntion and the functional reprogramming of monocyte-derived macrophages. MKP-1 deficiency accelerates atherosclerotic lesion formation by hyper-sensitizing monocytes to chemokine-induced recruitment, predisposing macrophages to M1 polarization, impaired autophagy and oxysterol-induced cell death. Reduced MKP-1 levels and activity in blood monocytes may therefore be a sensitive biomarker of increased risk of atherosclerosis.