Abstract | 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 ∼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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Authors | Konstantinos A Polyzos, Olga Ovchinnikova, Martin Berg, Roland Baumgartner, Hanna Agardh, John Pirault, Anton Gisterå, Alice Assinger, Andres Laguna-Fernandez, Magnus Bäck, Göran K Hansson, Daniel F J Ketelhuth |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 106
Issue 2
Pg. 295-302
(May 01 2015)
ISSN: 1755-3245 [Electronic] England |
PMID | 25750192
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected]. |
Chemical References |
- Apolipoproteins E
- Indoleamine-Pyrrole 2,3,-Dioxygenase
- Vascular Cell Adhesion Molecule-1
- Kynurenine
- tryptophan methyl ester
- Tryptophan
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Topics |
- Animals
- Apolipoproteins E
(genetics)
- Atherosclerosis
(metabolism)
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase
(antagonists & inhibitors, metabolism)
- Inflammation
(drug therapy, metabolism)
- Kynurenine
(metabolism)
- Mice, Knockout
- Tryptophan
(analogs & derivatives, pharmacology)
- Tunica Media
(metabolism)
- Vascular Cell Adhesion Molecule-1
(metabolism)
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