Group VIA Phospholipase A2 Mediates Enhanced Macrophage Migration in Diabetes Mellitus by Increasing Expression of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4

OBJECTIVE—We previously demonstrated that nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) mediates increased monocyte priming and chemotaxis under conditions of diabetic metabolic stress, and emerging data indicate that group VIA phospholipase A2 (iPLA2β) also participates in regulating monocyte chemotaxis. Here, we examined relationships between iPLA2β expression and Nox4 action in mouse peritoneal macrophages subjected to diabetic metabolic stress. APPROACH AND RESULTS—Increased iPLA2β expression and activity were observed in macrophages from low-density lipoprotein receptor knockout mice that were fed a high-fat diet, and this was associated with time-dependent increases in atherosclerotic lesion size and macrophage content. Incubating macrophages with 30 mmol/L D-glucose, 100 μg/mL low-density lipoprotein, or both (D-glucose+low-density lipoprotein) induced a robust increase in iPLA2β expression and activity and in cell migration in response to monocyte chemoattractant protein-1. The increases in iPLA2β activity and cell migration were prevented by a bromoenol lactone iPLA2β suicide inhibitor or an iPLA2β antisense oligonucleotide. Incubating macrophages under conditions that mimic diabetic metabolic stress ex vivo resulted in increased Nox4 expression and activity and hydrogen peroxide generation compared with controls. Bromoenol lactone prevented those effects without affecting Nox2 expression. Nox4 inhibition eliminated diabetic metabolic stress–induced acceleration of macrophage migration. Lysophosphatidic acid restored Nox4 expression, hydrogen peroxide generation, and migration to bromoenol lactone–treated cells, and a lysophosphatidic acid receptor antagonist abrogated iPLA2β-mediated increases in Nox4 expression. CONCLUSIONS—Taken together, these observations identify iPLA2β and lysophosphatidic acid derived from its action as critical in regulating macrophage Nox4 activity and migration in the diabetic state in vivo and under similar conditions ex vivo.