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Role of Kynurenine Pathway in Cardiovascular Diseases

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Targeting the Broadly Pathogenic Kynurenine Pathway

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Abstract

Atherosclerosis (AS) is a major pathologic sequel of obesity. It causes cardiovascular disease (CVD), the most common contributor to death in the Western world. A systemic chronic low-grade immune-mediated inflammation (scLGI) is substantially involved in AS and CVD. Pro-inflammatory cytokines released during cellular immunity play a major role, with the Th1-type cytokine interferon-gamma (IFN-γ) being a key mediator. Among other effects, IFN-γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, dendritic, and other cells, which ultimately decreases serum levels of the essential amino acid tryptophan (TRP). Hence, patients with CVD show increased serum kynurenine to tryptophan concentrations (KYN/TRP), a result of an increased TRP degradation. Importantly, a strong increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular outcomes. Moreover, an increased production of the pro-inflammatory adipokine leptin, in combination with IFN-γ and interleukin-6 (IL-6), represents a central link between obesity, AS, and CVD. Leptin has also been shown to be involved in a Th1-weighted T cell polarization.

Tryptophan is not only an important source for protein production but also counts for the generation of the neurotransmitter 5-hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. As with duration of scLGI, the availability of free serum TRP decreases, and brain serotonergic functions will be affected. The accumulation of neurotoxic KYN metabolites such as quinolinic acid, via NMDA glutamatergic stimulation, was also associated with the development of depression. Notably, depression had been brought into connection with CVD endpoints. Nevertheless, a secondary loop connecting excess adipose tissue with cardiovascular morbidity and mortality via scLGI appears to be more reliable in this context than a direct causal interaction.

Accelerated catabolism of TRP is also involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis. Hence, also hemoglobin production is decreased which reduces the oxygen supply. This constellation contributes to a worsening of ischemic vascular disease. Moreover, the influence of KYN and kynurenic acid on the complex processes involved in the destabilization of vascular atherosclerotic remains to be more elucidated.

In summary, within this chapter we show the impact of TRP breakdown pathways, and the related complex mechanisms on the prognosis and individual course of CVD. The analysis of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio may contribute to a better understanding of the interplay between immune-mediated inflammation, metabolic syndrome, mood disturbances, anemia, and destabilization of atherosclerotic plaques.

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Abbreviations

AS:

Atherosclerosis

CVD:

Cardiovascular diseases

GTP-CH1:

Guanosine triphosphate cyclohydrolase-1

HDL-C:

High-density lipoprotein cholesterol

IDO:

Indoleamine 2,3-dioxygenase

iNOS:

Inducible nitric oxide synthase

IFN-γ:

Interferon-γ

KYN:

Kynurenine

LDL-C:

Low-density lipoprotein cholesterol

MetS:

Metabolic syndrome

MI:

Myocardial infarction

NO:

Nitric oxide

ROS:

Reactive oxygen species

T5H:

Tryptophan 5-hydroxylase

TDO:

Tryptophan 2,3-dioxygenase

TNF-α:

Tumor necrosis factor-α

TRP:

Tryptophan

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Authors and Affiliations

  1. Research Unit on Lifestyle and Inflammation-associated Risk Biomarkers, Clinical Institute of Medical and Chemical Laboratory Diagnosis, Medical University of Graz, Auenbruggerplatz 30, 8036, Graz, Austria

    Harald Mangge

  2. Department of Psychiatry, Medical University of Graz, Graz, Austria

    Eva Reininghaus

  3. Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Graz, Austria

    Dietmar Fuchs

Authors
  1. Harald Mangge
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  2. Eva Reininghaus
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  3. Dietmar Fuchs
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Correspondence to Harald Mangge .

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Editors and Affiliations

  1. Chairman, Department of Neurosurgery, Wayne State University, Detroit, Michigan, USA

    Sandeep Mittal

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Mangge, H., Reininghaus, E., Fuchs, D. (2015). Role of Kynurenine Pathway in Cardiovascular Diseases. In: Mittal, S. (eds) Targeting the Broadly Pathogenic Kynurenine Pathway. Springer, Cham. https://doi.org/10.1007/978-3-319-11870-3_10

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