Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?

Fazio, Francesco; Carrizzo, Albino; Lionetto, Luana; Damato, Antonio L.; Capocci, Luca; Ambrosio, Mariateresa; Battaglia, Giuseppe; Bruno, Valeria; Madonna, Michele; Simmaco, Maurizio; Nicoletti, Ferdinando; Vecchione, Carmine

doi:10.3389/fphar.2017.00214

Cited by 37 publications

(28 citation statements)

References 32 publications

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“…We also showed that commercial kynurenine relaxed pre-constricted arteries, which suggested that kynurenine is an endotheliumderived relaxant factor 6 . Although others have since confirmed these findings 11,12 , we noticed that recently purchased kynurenine no longer caused arterial relaxation, and that HPLC-purified kynurenine and NFK also failed to relax naïve mouse arteries (Fig. 1b).…”

mentioning

confidence: 56%

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Stanley

Maghzal

Ayer

et al. 2019

Nature

112

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Singlet molecular oxygen ( 1 O 2 ) has well-established roles in photosynthetic plants, bacteria and fungi 1-3 , but not in mammals. Chemically generated 1 O 2 oxidizes the amino acid tryptophan to precursors of a key metabolite called N-formylkynurenine 4 , while enzymatic oxidation of tryptophan to N-formylkynurenine is catalyzed by a family of dioxygenases, including indoleamine 2,3-dioxygenase 1 5 . Under inflammatory conditions, this hemecontaining enzyme becomes expressed in arterial endothelial cells, where it contributes to the regulation of blood pressure 6 . However, whether indoleamine 2,3-dioxygenase 1 forms 1 O 2 and whether this contributes to blood pressure control is unknown. Here we show that arterial indoleamine 2,3-dioxygenase 1 regulates blood pressure via formation of 1 O 2 . We observed that in the presence of hydrogen peroxide, the enzyme generates 1 O 2 and that this is associated with the stereoselective oxidation of L-tryptophan to a tricyclic hydroperoxide via a previously unrecognized oxidative activation of the dioxygenase activity. The tryptophanderived hydroperoxide acts as a hitherto undiscovered signaling molecule in vivo, which induces arterial relaxation and decreases blood pressure dependent on cysteine residue 42 of protein kinase G1α. Our findings demonstrate a pathophysiological role for 1 O 2 in mammals through formation of an amino acid-derived hydroperoxide that regulates vascular tone and blood pressure under inflammatory conditions. Several small molecules, such as nitric oxide and hydrogen peroxide (H 2 O 2 ) regulate cellular signaling via interaction with proteins containing redox active metals and/or cysteine residues. Of these molecules, nitric oxide, formed from L-arginine by endothelial nitric oxide synthase, is an important regulator of vascular tone 7 . Sustained increases in nitric oxide synthesis by inducible nitric oxide synthase, as observed in pathological settings such as sepsis, are associated with profound hypotension 8 . Paradoxically, inhibitors of the nitric oxide pathway have generally failed to ameliorate severe septic shock 9,10 , suggesting involvement of additional mediators of hypotension.Based on functional similarity with the metabolism of L-arginine by nitric oxide synthase, we 3 reported previously that metabolism of L-tryptophan (Trp) to N-formylkynurenine (NFK) and kynurenine by endothelial indoleamine 2,3-dioxygenase 1 (IDO1) ( Fig. 1a) contributes to the regulation of vascular tone and blood pressure in inflammation 6 . We also showed that commercial kynurenine relaxed pre-constricted arteries, which suggested that kynurenine is an endotheliumderived relaxant factor 6 . Although others have since confirmed these findings 11,12 , we noticed that recently purchased kynurenine no longer caused arterial relaxation, and that HPLC-purified kynurenine and NFK also failed to relax naïve mouse arteries ( Fig. 1b). However, purified Trp relaxed pre-constricted mouse abdominal aortas that expressed IDO1, irrespective of whether IDO1 expression was...

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mentioning

confidence: 56%

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Stanley

Maghzal

Ayer

et al. 2019

Nature

112

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“…The other data from studies both on animals and patients indicate that KYNA and XA may also have vasorelaxation and antihypertension properties (Figure 1). 143,144,169 These data indicate that the components of the kynurenine pathway can play diverse, sometimes opposite roles in the development of hypertension. Their accumulation in the course of chronic renal failure seems to be at least partly associated with the development of CKD-related hypertension.…”

Section: The Importance Of Accumulation Of the Kynurenine Pathway Commentioning

confidence: 99%

“…They are involved in the pathogenesis of numerous neurodegenerative diseases. 19,29,30,170 Also, the development of chronic renal insufficiency, accompanied by the accumulation of these compounds, is associated with the worsening of neurological disturbances. 29,30,43 Alterations in the TRP, KYN, 3-HKYN, and QA concentrations were observed within CNS homogenates in uremic rats.…”

Section: The Impact Of the Accumulation Of The Kynurenine Pathway Metmentioning

confidence: 99%

Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next?

Mor

Kałaska

Pawlak

2020

Int J�Tryptophan�Res

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Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD.

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“…Notably, however, recent studies have also begun to indicate a physiological role of the metabolite in mammals. Thus, XA, which exhibits antioxidant properties both in vitro and in vivo (Christen et al, 1990, Murakami et al, 2001, Lima et al, 2012), has vasorelaxing properties (Fazio et al, 2017a), attenuates tetrahydrobiopterine biosynthesis (Haruki et al, 2016) and may regulate glucose homeostasis (Favennec et al, 2016). Notably, XA induces apoptotic cell death in cultured lens epithelial cells (Malina et al, 2002) and has been repeatedly linked to various pathological events, including type 2 diabetes (Oxenkrug, 2015).…”

Section: Introductionmentioning

confidence: 99%

Xanthurenic Acid Formation from 3-Hydroxykynurenine in the Mammalian Brain: Neurochemical Characterization and Physiological Effects

Sathyasaikumar

Tararina

et al. 2017

Neuroscience

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Xanthurenic acid (XA), formed from 3-hydroxykynurenine (3-HK) in the kynurenine pathway of tryptophan degradation, may modulate glutamatergic neurotransmission by inhibiting the vesicular glutamate transporter and/or activating Group II metabotropic glutamate receptors. Here we examined the molecular and cellular mechanisms by which 3-HK controls the neosynthesis of XA in rat, mouse and human brain, and compared the physiological actions of 3-HK and XA in the rat brain. In tissue homogenates, XA formation from 3-HK was observed in all three species and traced to a major role of kynurenine aminotransferase II (KAT II). Transamination of 3-HK to XA was also demonstrated using human recombinant KAT II. Neosynthesis of XA was significantly increased in the quinolinate-lesioned rat striatum, indicating a non-neuronal localization of the process. Studies using rat cortical slices revealed that newly produced XA is rapidly released into the extracellular compartment, and that XA biosynthesis can be manipulated experimentally in the same way as the production of kynurenic acid from kynurenine (omission of Na+ or glucose, depolarizing conditions, or addition of 2-oxoacids). The synthesis of XA from 3-HK was confirmed in vivo by striatal microdialysis. In slices from the rat hippocampus, both 3-HK and XA reduced the slopes of dentate gyrus field EPSPs. The effect of 3-HK was reduced in the presence of the KAT inhibitor aminooxyacetic acid. Finally, both 3-HK and XA reduced the power of gamma-oscillatory activity recorded from the hippocampal CA3 region. Endogenous XA, newly formed from 3-HK, may therefore play a physiological role in attentional and cognitive processes.

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Vasorelaxing Action of the Kynurenine Metabolite, Xanthurenic Acid: The Missing Link in Endotoxin-Induced Hypotension?

Cited by 37 publications

References 32 publications

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation

Kynurenine Pathway in Chronic Kidney Disease: What’s Old, What’s New, and What’s Next?

Xanthurenic Acid Formation from 3-Hydroxykynurenine in the Mammalian Brain: Neurochemical Characterization and Physiological Effects

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