Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

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: Aging; Aortic aneurysm; Atherosclerosis; Diabetes; Kynurenine pathway; Obesity; Tryptophan.

Fig. 1

Major enzymes, catabolites, and inhibitors in tryptophan metabolism. Tryptophan is metabolized via two major pathways, kynurenine pathway and serotonin/melatonin pathway. 3-HAO 3-hydroxyanthranilate 3,4-dioxygenase, ACMSD 2-amino-3-carboxymuconate semialdehyde decarboxylase, FAD flavin adenine dinucleotide, HIOMT hydroxyindole O-methyltransferase, oMBA o-Methoxybenzoyalanine, QPRT quinolinate phosphoribosyltransferase, TPH tryptophan hydroxylase. Refer to the text for the expanded form of abbreviations

Fig. 2

Abnormal kynurenine pathway and atherogenesis. Elevation of 3-hydroxyanthranilic acid (3-HAA) or anthranilic acid (AA) by IDO activation inhibits vascular inflammation and subsequent atherosclerosis in LDLr^−/− or ApoE^−/− mice. However, kynurenic acid (KA) elevation by IDO upregulation enhances vascular inflammation and exacerbates atherogenesis in LDLr^−/−mice (blue box). MØ macrophage, PKA protein kinase A, Treg regulatory T cell. For definitions of other abbreviations, please see the main text. ┴, inhibits