Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr-/- mice

The pathogenesis of atherosclerosis is accelerated by oxidative stress, which produces lipid peroxidation. Among the products of lipid peroxidation are highly reactive dicarbonyls that covalently modify proteins. We investigated the impact of treatment with the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in hyperlipidemic Ldlr-/- mice, a model of familial hypercholesterolemia (FH). Compared to mice treated with vehicle, 2-HOBA significantly decreased atherosclerosis in hypercholesterolemic Ldlr-/- mice by 31% in the proximal aortas and 60% in en face aortas, in the absence of changes in blood lipid levels. 2-HOBA reduced malondialdehyde (MDA) content in HDL, LDL, and in the atherosclerotic lesions. Consuming a Western diet increased plasma MDA-apoAI adduct levels in Ldlr-/- mice. 2-HOBA inhibited MDA-apoAI formation and increased the capacity of the mouse HDL to reduce macrophage cholesterol stores. Furthermore, 2-HOBA diminished oxidative stress-induced inflammatory responses in macrophages and reduced the number of TUNEL-positive cells in atherosclerotic lesions by 72%. Importantly, 2-HOBA enhanced efferocytosis and promoted characteristics of stable plaque formation in mice as evidenced by a 69% (p