Anti-inflammatory salicylate beneficially modulates pre-existing atherosclerosis through quenching of NF-κB activity and lowering of cholesterol

Abstract Objective Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic lesions. Putative beneficial effects of salicylate, an inhibitor of NF-κB activation, were studied in mice with established lesions. Methods ApoE*3-Leiden mice received a high-cholesterol diet (HC) to establish atherosclerotic lesions. Reference mice (REF) were sacrificed to determine the lesion area at the start of two interventions. In one intervention group HC diet feeding was continued, but the diet contained salicylate (HC + SAL). As salicylate not only quenches inflammation but also reduces plasma cholesterol, a second intervention group was fed a low-cholesterol diet (LC) resulting in cholesterol levels comparable to HC + SAL. The effects of these interventions on lesion area and composition were assessed after 8 and 16 weeks. Results HC + SAL markedly reduced hepatic NF-κB activity compared to REF, and was significantly more effective than LC diet feeding. HC + SAL and LC also quenched aortic NF-κB activity. While continuing HC diet typically further increases total lesion area, 16 weeks of intervention with HC + SAL and LC halted further disease progression and resulted in lesion sizes comparable to that of REF. At the same time, lesion composition was significantly improved, particularly with salicylate. Strikingly, HC + SAL resulted in a lower lesional macrophage content and a greater plaque stability index (ratio of collagen to macrophage area) than LC. Conclusion Anti-inflammatory salicylate reduces atherosclerotic macrophage content and increases lesion stability of pre-existing plaques through quenching of NF-κB activity and reducing plasma cholesterol.