National Cholesterol Awareness Month Article Integrative Physiology and Experimental Medicine Orally Administered Eicosapentaenoic Acid Induces Rapid Regression of Atherosclerosis Via Modulating the Phenotype of Dendritic Cells in LDL Receptor-Deficient Mice

Objective—Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. Methods and Results—LDL-receptor– deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (Ϫ22.7%, PϽ0.05) and decreased the content of macrophages, CD4 ϩ T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c ϩ CD80 Ϫ CD86 Ϫ), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4 ϩ T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. Conclusion—In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence. E vidence for atherosclerosis regression in humans has been reported. 1,2 Although lowering of plasma lipid levels is a major driving force, the mechanisms that promote lesion regression are not clear. Recent clinical evidence indicated that lowering elevated high-sensitive C-reactive protein levels in plasma with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) significantly reduced the incidence of major cardiovascular events in nor-molipidemic healthy persons. 3 These data indicate that statins, in addition to their aggressive lipid lowering effect, may also be a hopeful therapeutic strategy for inhibiting cardiovascular events via stabilization or regression of ath-erosclerotic plaques through their antiinflammatory actions. Eicosapentaenoic acid (EPA), a long-chain n-3 fatty acid, was reported to have beneficial effects on cardiovas-cular diseases. 4,5 We have also demonstrated that the use of highly purified EPA, in addition to statins, prevented cardiovascular events in Japanese hypercholesterolemic patients. 6 On the basis of these findings, we hypothesized that EPA could regress atherosclerosis. Recent studies demonstrated that a metabolite of EPA inhibited the maturation of dendritic cells (DCs), downregulated co-stimulatory molecules, and induced indoleamine 2,3-diox-ygenase (IDO). 7 IDO, an enzyme involved in tryptophan catabolism, breaks down tryptophan required for T cell proliferation, and its induction is …