Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice.
OBJECTIVE
Atherosclerosis is a chronic inflammatory disease that is initiated by the retention and accumulation of low-density lipoprotein in the artery, leading to maladaptive response of cells from the immune system and vessel wall. Strong evidence implicates indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the kynurenine pathway of tryptophan (Trp) degradation, with immune regulation and anti-inflammatory mechanisms in different diseases. However, the role of IDO and the endogenous degradation of Trp have never been directly examined in atherosclerosis development. We used the IDO inhibitor 1-methyl-Trp (1-MT) to determine the role of IDO-mediated Trp metabolism in vascular inflammation and atherosclerosis.


RESULTS
Apoe(-/-) mice were treated with 1-MT in drinking water for 8 weeks. Systemic IDO inhibition led to a significant increase in atherosclerotic lesions that were ∼58 and 54% larger in the aortic arch and root, respectively. 1-MT treatment enhanced vascular inflammation, up-regulated VCAM-1 and CCL2, and increased CD68 macrophage accumulation into the plaque. Notably, the rise in VCAM-1 expression was not limited to the plaque but also found in smooth muscle cells (SMCs) of the tunica media. Furthermore, we found that IDO-dependent Trp metabolism by SMCs regulates VCAM-1 expression, and that 1-MT-induced acceleration of atherosclerosis and vascular inflammation can be reversed by exogenous administration of the Trp metabolite 3-hydroxyanthranilic acid (3-HAA).


CONCLUSIONS
IDO-mediated Trp metabolism regulates vascular inflammation and plaque formation in hypercholesterolaemic Apoe(-/-) mice. Our data establish that this pathway plays a major role in the pathological process of atherogenesis.
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Konstantinos A
KA
Polyzos
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Olga
O
Ovchinnikova
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Martin
M
Berg
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Roland
R
Baumgartner
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Hanna
H
Agardh
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
John
J
Pirault
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Anton
A
Gisterå
Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Alice
A
Assinger
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Andres
A
Laguna-Fernandez
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Magnus
M
Bäck
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden.
Göran K
GK
Hansson
Department of Medicine, Experimental Cardiovascular Research Unit, Center for Molecular Medicine, L8:03, Karolinska University Hospital, Stockholm S-17176, Sweden daniel.ketelhuth@ki.se.
Daniel F J
DF
Ketelhuth
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D018345:Mice, Knockout; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D017540:Tunica Media / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001057:Apolipoproteins E; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D019010:Vascular Cell Adhesion Molecule-1; D007737:Kynurenine; C028129:tryptophan methyl ester; D014364:Tryptophan
3-Hydroxyanthranilic acid (3-HAA); Atherosclerosis; Indoleamine 2,3-dioxygenase (IDO); Inflammation; Kynurenine