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Cellular and Molecular Life Sciences

, Volume 74, Issue 16, pp 2899–2916 | Cite as

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

  • Ping SongEmail author
  • Tharmarajan Ramprasath
  • Huan Wang
  • Ming-Hui Zou
Review

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.

Keywords

Tryptophan Kynurenine pathway Aortic aneurysm Atherosclerosis Aging Obesity Diabetes 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Center for Molecular and Translational MedicineGeorgia State UniversityAtlantaUSA

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