Journal
CARDIOVASCULAR RESEARCH
Volume 106, Issue 2, Pages 295-302Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvv100
Keywords
Indoleamine 2,3-dioxygenase (IDO); 3-Hydroxyanthranilic acid (3-HAA); Kynurenine; Inflammation; Atherosclerosis
Categories
Funding
- Swedish Heart-Lung Foundation
- Karolinska Institute Cardiovascular Program Career Development Grant
- CERIC Linnaeus Program [349-2007-8703]
- Swedish Research Council-Medicine [521-2012-2440, K2013-65X-06816]
- Swedish Foundation for Strategic Research-SSF
- Stockholm County Council-ALF
- Vinnova Foundation
- AkeWibergs Stiftelse
- Stiftelsen for Gamla Tjanarinnor
- Stiftelsen for alderssjukdomar-Kl
- Stiftelsen Professor Nanna Svartz fond
- KI fond
- European Union projects (Molstroke, AtheroRemo)
- Austrian Science Fund [FWF-P24978]
- Alexander S. Onassis Foundation
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Aims 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. Methods and 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 similar to 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). Conclusion 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.
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