Abstract 368: Inhibition of Ido-mediated Tryptophan Metabolism Aggravates Atherosclerosis in Hypercholesterolemic Mice

Introduction: Indoleamine 2,3-dioxygenase (IDO), an enzyme catalyzing the first step of tryptophan (Trp) degradation along the kynurenine pathway, has been shown to control autoimmunity and inflammation. Pharmacological inhibition of IDO by 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO, aggravates disease in several chronic inflammation models. Yet, the role of IDO-mediated Trp metabolism in the pathogenesis of atherosclerosis is unknown. Hypothesis: We assessed the hypothesis that inhibition of tryptophan metabolism affects the development of atherosclerosis in hypercholesterolemic Apoe-/- mice. Methods/Results: Twelve-week old Apoe-/- mice were treated with 1-MT in the drinking water for 8 weeks. Systemic IDO inhibition led to significantly larger atherosclerotic lesions in the aortic root (0.211± 0.024 vs 0.118± 0.025 mm2; mean ± SEM for 1-MT and controls, respectively; n=9-10). IDO inhibition resulted in increased aortic mRNA levels of TNF, MCP-1, and VCAM-1. Immunohistochemical staining ...