Nonenzymatic Glycation Impairs the Antiinflammatory Properties of Apolipoprotein A-I

Abstract

Objective—The goal of this study was to investigate the effects of nonenzymatic glycation on the antiinflammatory properties of apolipoprotein (apo) A-I.Methods and Results—Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-I_N), lipid-free apoA-I nonenzymatically glycated by incubation with methylglyoxal (apoA-I_{Glyc in vitro}), nonenzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-I_{Glyc in vivo}), discoidal reconstituted high-density lipoproteins (rHDL) containing phosphatidylcholine and apoA-I_N, (A-I_N)rHDL, or apoA-I_{Glyc in vitro}, (A-I_{Glyc in vitro})rHDL. At 24 hours postinfusion, acute vascular inflammation was induced by inserting a nonocclusive, periarterial carotid collar. The animals were euthanized 24 hours after the insertion of the collar. The collars caused intima/media neutrophil infiltration and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). ApoA-I_Ninfusion decreased neutrophil infiltration and VCAM-1 and ICAM-1 expression by 89%, 90%, and 66%, respectively. The apoA-I_{Glyc in vitro}infusion decreased neutrophil infiltration by 53% but did not reduce VCAM-1 or ICAM-1 expression. ApoA-I_{Glyc in vivo}did not inhibit neutrophil infiltration or adhesion molecule expression. (A-I_{Glyc in vitro})rHDL also inhibited vascular inflammation less effectively than (A-I_N)rHDL. The reduced antiinflammatory properties of nonenzymatically glycated apoA-I were attributed to a reduced ability to inhibit nuclear factor-κB activation and reactive oxygen species formation.Conclusion—Nonenzymatic glycation impairs the antiinflammatory properties of apoA-I.