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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1283.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

Glucose Metabolism Is Required for Oxidized LDL–Induced Macrophage Survival

Role of PI3K and Bcl-2 Family Proteins

Caryn L. Elsegood; Margaret Chang; Wendy Jessup; Glen M. Scholz; John A. Hamilton

From the Arthritis and Inflammation Research Centre and Cooperative Research Centre for Chronic Inflammatory Diseases (C.L.E., M.C., G.M.S., J.A.H.), The University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Australia; and Macrophage Biology Group, Centre for Vascular Research (W.J.), University of New South Wales, Kensington, Sydney, Australia.

Correspondence to Caryn L. Elsegood, Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia. E-mail c.elsegood{at}unimelb.edu.au

Abstract

Objective— Oxidized low-density lipoprotein (oxLDL) induces survival of colony stimulating factor-1 (CSF-1)-dependent macrophages in vitro. Because atherosclerotic lesion–associated macrophages take up large amounts of glucose, we investigated whether, and how, oxLDL promotes glucose uptake and how glucose metabolism regulates oxLDL-induced macrophage survival.

Methods and Results— OxLDL-induced macrophage survival required glucose metabolism. OxLDL stimulated 2 phases of glucose uptake, namely acute and chronic, which required PI3K but not MEK1/2 activity. PI3K appeared to regulate glucose transport via glucose transporter affinity and/or mobilization. OxLDL also maintained levels of the prosurvival proteins, Bcl-2 and Bcl-x_L, after CSF-1 had been removed through a combination of mechanisms including transcription, translation, and protein stabilization. Significantly, inhibition of glucose metabolism reduced Bcl-2 and Bcl-x_L protein levels. MEK1/2 and PI3K activities were also required for oxLDL-induced Bcl-2 and Bcl-x_L mRNA upregulation.

Conclusions— These results suggest that oxLDL enhances macrophage survival in the absence of CSF-1 by inducing PI3K-dependent glucose uptake, which is metabolized to maintain Bcl-2 and Bcl-x_L protein levels.

Atherosclerotic lesion-associated macrophages take up large amounts of glucose. Oxidized LDL, which is found in atherosclerotic lesions, enhances in vitro macrophage survival by inducing PI3K-dependent glucose uptake. Metabolism of the glucose is required to maintain Bcl-2 and Bcl-x_L protein levels, and hence for macrophage survival.

Key Words: macrophage • oxidized LDL • glucose • survival • Bcl-2 family proteins