Early kynurenine pathway activation following cardiac arrest in rats, pigs, and humans

Ristagno, Giuseppe; Fries, Michael; Brunelli, Laura; Fumagalli, Francesca; Bagnati, Renzo; Russo, Ilaria; Staszewsky, Lidia; Masson, Serge; Volti, Giovanni Li; Zappalà, Agata; Derwall, Matthias; Brücken, Anne; Pastorelli, Roberta; Latini, Roberto

doi:10.1016/j.resuscitation.2013.06.002

Cited by 37 publications

(41 citation statements)

References 35 publications

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“…Notably, KYNA is elevated in survivors of cardiac arrest—a condition of systemic ischemia—in both animal models and in humans (Ristagno et al, 2013). Also, the KYNA precursor, KYN, is induced in hypoxic cells as part of a ‘catabolic signature’ of hypoxia (Frezza et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Olenchock¹,

Moslehi²,

Baik³

et al. 2016

Cell

114

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SUMMARY Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the HIF transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.

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Section: Discussionmentioning

confidence: 99%

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Olenchock¹,

Moslehi²,

Baik³

et al. 2016

Cell

114

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“…Persisted high plasma KYNA concentration has been noted in non-survived stroke traumatic patients and patients, who died after resuscitation (Darlington et al 2007; Ploder et al 2009; Ristagno et al 2013). Significantly higher plasma KYNA concentration has been found in carotid surgery patients with postoperative neurological dysfunctions (Terlecki et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Plasma Kynurenic Acid Concentration in Patients Undergoing Cardiac Surgery: Effect of Anaesthesia

Kotlińska-Hasiec

Nowicka-Stążka

Parada-Turska

et al. 2014

Arch. Immunol. Ther. Exp.

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Increases in plasma kynurenic acid (KYNA) concentration relate to the severity of inflammation. The aim of this study was to analyse changes in plasma KYNA concentration and neutrophil/lymphocyte ratio (NLR) in cardiac surgery patients. Additionally, the effect of anaesthesia was analysed. Adult cardiac surgery patients under intravenous general anaesthesia were studied. Additionally, some patients received sevoflurane (SEV) prior to cardiopulmonary bypass. Plasma KYNA concentration and NLR were measured before anaesthesia, just after surgery and on postoperative days 1, 2 and 3. Patients were assigned to two groups: patients who did not receive SEV (NonSEV group) and patients who received SEV (SEV group). Forty-three patients were studied. Twenty-four of them received SEV. KYNA increased immediately after surgery and remained elevated through postoperative day 3 in the NonSEV group, whereas it was similar to the preoperative concentration in the SEV group. NLR increased immediately after surgery in both groups, and higher values were noted in the NonSEV group than in the SEV group at postoperative days 2 and 3. Plasma KYNA concentration correlated with NLR in the NonSEV group. Cardiac surgery caused an increase in NLR. Plasma KYNA increased in the NonSEV group and correlated with NLR. Administration of SEV inhibited the increase in KYNA, most likely due to its anti-inflammatory properties.

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“…The KTR may serve as a short-term measurement of immune activation and therefore permit an estimate of the extent of immune activation. Moreover, the Kyn pathway has been shown to be activated after cardiac arrest in rats, pigs, and humans(214). Decreases in Trp occurred during the post-resuscitation period and were accompanied by significant increases in its major metabolites, 3-HAA and KYNA, in each species.…”

Section: The Abnormal Kynurenine Pathway Links Oxidative Stress Imentioning

confidence: 99%

Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

Liu²,

et al. 2015

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The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism, and it contributes to several fundamental biological processes. Trp is constitutively oxidized by tryptophan 2, 3-dioxygenase in liver cells. In other cell types, it is catalyzed by an alternative inducible indoleamine-pyrrole 2, 3-dioxygenase (IDO) under certain pathophysiological conditions, which consequently increases the formation of Kyn metabolites. IDO is up-regulated in response to inflammatory conditions as a novel marker of immune activation in early atherosclerosis. Besides, IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis. In particular, Kyn, 3-hydroxykynurenine, and quinolinic acid are positively associated with inflammation, oxidative stress (SOX), endothelial dysfunction, and carotid artery intima-media thickness values in end-stage renal disease patients. Moreover, IDO is a potential novel contributor to vessel relaxation and metabolism in systemic infections, which is also activated in acute severe heart attacks. The Kyn pathway plays a key role in the increased prevalence of cardiovascular disease by regulating inflammation, SOX, and immune activation.

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Early kynurenine pathway activation following cardiac arrest in rats, pigs, and humans

Cited by 37 publications

References 35 publications

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Plasma Kynurenic Acid Concentration in Patients Undergoing Cardiac Surgery: Effect of Anaesthesia

Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

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