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Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

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Abstract

Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine amino-transferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP enzyme inhibitors against CVD is briefly discussed.

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Abbreviations

1-MT:

1-methyl tryptophan

3-HAA:

3-hydroxyanthranilic acid

3-HK:

3-hydroxykynurenine

AA:

Anthranilic acid

AAA:

Abdominal aortic aneurysm

AHR:

Aryl hydrocarbon receptor

Ang II:

Angiotensin II

DCs:

Dendritic cells

HFD:

High-fat diet

IDO1:

Indoleamine-2,3-dioxygenase 1

IFN-γ:

Interferon-gamma

IR:

Insulin resistance

KA:

Kynurenic acid

KAT:

Kynurenine amino-transferase

KMO:

Kynurenine-3-monooxygenase

KYNU:

Kynureninase

KP:

Kynurenine pathway

Kyn:

Kynurenine

MMPs:

Matrix metalloproteinases

oxLDL:

Oxidized low-density lipoprotein

pDCs:

Plasmacytoid dendritic cells

PLP:

Pyridoxal 5′-phosphate

QA:

Quinolinic acid

TDO:

Tryptophan 2,3-dioxygenase

Trp:

Tryptophan

VCAM-1:

Vascular cell adhesion molecule-1

VSMC:

Vascular smooth muscle cell

XA:

Xanthurenic acid

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Acknowledgements

This study was supported by funding from the following agencies: National Institutes of Health RO1 (HL132500, HL128014, HL110488, HL080499, HL089920, AG047776, and CA213022). This work is in part supported by the Georgia Research Alliance. Dr. Zou is a Georgia Research Alliance Eminent Scholar in Molecular Medicine.

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  1. Center for Molecular and Translational Medicine, Georgia State University, 157 Decatur Street SE, Atlanta, GA, 30303, USA

    Ping Song, Tharmarajan Ramprasath, Huan Wang & Ming-Hui Zou

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  1. Ping Song
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  2. Tharmarajan Ramprasath
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  3. Huan Wang
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  4. Ming-Hui Zou
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Correspondence to Ping Song.

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Song, P., Ramprasath, T., Wang, H. et al. Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell. Mol. Life Sci. 74, 2899–2916 (2017). https://doi.org/10.1007/s00018-017-2504-2

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  • DOI: https://doi.org/10.1007/s00018-017-2504-2

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