Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice

Cardiovasc Res. 2015 May 1;106(2):295-302. doi: 10.1093/cvr/cvv100. Epub 2015 Mar 5.

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.

Keywords: 3-Hydroxyanthranilic acid (3-HAA); Atherosclerosis; Indoleamine 2,3-dioxygenase (IDO); Inflammation; Kynurenine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / genetics
  • Atherosclerosis / metabolism*
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Kynurenine / metabolism*
  • Mice, Knockout
  • Tryptophan / analogs & derivatives*
  • Tryptophan / pharmacology
  • Tunica Media / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Apolipoproteins E
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Vascular Cell Adhesion Molecule-1
  • Kynurenine
  • tryptophan methyl ester
  • Tryptophan