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 of plaques showed increased CD68+ macrophage infiltration and VCAM-1 expression in 1-MT-treated mice. Additionally, IDO inhibition increased VCAM-1 expression in the smooth muscle cells (SMCs) of the tunica media. Moreover, we found that IDO-dependent Trp metabolism by SMCs regulates VCAM-1 expression, and that 1-MT-induced acceleration of atherosclerosis can be reversed by exogenous administration of the downstream Trp metabolite 3-hydroxyanthranilic acid (3-HAA). Importantly, 3-HAA supplementation reversed the 1-MT-induced VCAM-1 expression in the medial compartment.
Conclusion: IDO-mediated Trp metabolism plays a major role in vascular inflammation and atherosclerosis in Apoe-/- mice.
Author Disclosures: K.A. Polyzos: None. O. Ovchinnikova: None. M. Berg: None. R. Baumgartner: None. H. Agardh: None. J. Pirault: None. A. Gisterå: None. A. Assinger: None. A. Laguna Fernandez: None. M. Bäck: None. G.K. Hansson: Ownership Interest; Modest; Holds patents on the use of 3-HAA for the prevention and treatment of hyperlipidemia and its complications. D.F.J. Ketelhuth: Ownership Interest; Modest; Holds patents on the use of 3-HAA for the prevention and treatment of hyperlipidemia and its complications..
- © 2015 by American Heart Association, Inc.