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

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*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftCardiovascular Research
Vol/bind106
Udgave nummer2
Sider (fra-til)295-302
ISSN0008-6363
DOI
StatusUdgivet - 1. maj 2015
Udgivet eksterntJa

Fingeraftryk

Indoleamine-Pyrrole 2,3,-Dioxygenase
Tryptophan
Vascular Cell Adhesion Molecule-1
3-Hydroxyanthranilic Acid
Kynurenine
LDL Lipoproteins
Immune System
Macrophages
Enzymes

Bibliografisk note

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Citer dette

Polyzos, Konstantinos A ; Ovchinnikova, Olga ; Berg, Martin ; Baumgartner, Roland ; Agardh, Hanna ; Pirault, John ; Gisterå, Anton ; Assinger, Alice ; Laguna-Fernandez, Andres ; Bäck, Magnus ; Hansson, Göran K ; Ketelhuth, Daniel F J. / Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice. I: Cardiovascular Research. 2015 ; Bind 106, Nr. 2. s. 295-302.
@article{17c3545f43134a9dbab6387156cfb016,
title = "Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice",
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 = "Animals, Apolipoproteins E/genetics, Atherosclerosis/metabolism, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors, Inflammation/drug therapy, Kynurenine/metabolism, Mice, Knockout, Tryptophan/analogs & derivatives, Tunica Media/metabolism, Vascular Cell Adhesion Molecule-1/metabolism",
author = "Polyzos, {Konstantinos A} and Olga Ovchinnikova and Martin Berg and Roland Baumgartner and Hanna Agardh and John Pirault and Anton Gister{\aa} and Alice Assinger and Andres Laguna-Fernandez and Magnus B{\"a}ck and Hansson, {G{\"o}ran K} and Ketelhuth, {Daniel F J}",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\circledC} The Author 2015. For permissions please email: journals.permissions@oup.com.",
year = "2015",
month = "5",
day = "1",
doi = "10.1093/cvr/cvv100",
language = "English",
volume = "106",
pages = "295--302",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Heinemann",
number = "2",

}

Polyzos, KA, Ovchinnikova, O, Berg, M, Baumgartner, R, Agardh, H, Pirault, J, Gisterå, A, Assinger, A, Laguna-Fernandez, A, Bäck, M, Hansson, GK & Ketelhuth, DFJ 2015, 'Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice', Cardiovascular Research, bind 106, nr. 2, s. 295-302. https://doi.org/10.1093/cvr/cvv100

Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice. / Polyzos, Konstantinos A; Ovchinnikova, Olga; Berg, Martin; Baumgartner, Roland; Agardh, Hanna; Pirault, John; Gisterå, Anton; Assinger, Alice; Laguna-Fernandez, Andres; Bäck, Magnus; Hansson, Göran K; Ketelhuth, Daniel F J.

I: Cardiovascular Research, Bind 106, Nr. 2, 01.05.2015, s. 295-302.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice

AU - Polyzos, Konstantinos A

AU - Ovchinnikova, Olga

AU - Berg, Martin

AU - Baumgartner, Roland

AU - Agardh, Hanna

AU - Pirault, John

AU - Gisterå, Anton

AU - Assinger, Alice

AU - Laguna-Fernandez, Andres

AU - Bäck, Magnus

AU - Hansson, Göran K

AU - Ketelhuth, Daniel F J

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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.

AB - 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.

KW - Animals

KW - Apolipoproteins E/genetics

KW - Atherosclerosis/metabolism

KW - Humans

KW - Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors

KW - Inflammation/drug therapy

KW - Kynurenine/metabolism

KW - Mice, Knockout

KW - Tryptophan/analogs & derivatives

KW - Tunica Media/metabolism

KW - Vascular Cell Adhesion Molecule-1/metabolism

U2 - 10.1093/cvr/cvv100

DO - 10.1093/cvr/cvv100

M3 - Journal article

C2 - 25750192

VL - 106

SP - 295

EP - 302

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

ER -