Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension

Jasiewicz, Małgorzata; Moniuszko, Marcin; Pawlak, Dariusz; Knapp,; Rusak, Małgorzata; Kazimierczyk, Remigiusz; Musiał, Włodzimierz J.; Dąbrowska, Milena; Kamiński, Karol

doi:10.1136/heartjnl-2015-308581

Cited by 31 publications

(36 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Kynurenine exerts immune regulatory functions, which might be relevant in pulmonary hypertension (8,19,23,25). In the systemic circulation, IDO expression is increased in smallresistance vessels during inflammation and, consequently, might be involved in vasomotor collapse in sepsis.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Importance of kynurenine in pulmonary hypertension

Nagy

Nagaraj

Meinitzer

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

The tryptophan metabolite kynurenine is significantly increased in pulmonary arterial hypertension (PAH) patients, and it is a potent vasodilator of systemic arteries. Our aim was to investigate the role of kynurenine in the pulmonary circulation. Serum tryptophan, kynurenine, and kynurenic acid levels were measured in 20 idiopathic PAH (IPAH) patients, 20 healthy controls, and 20 patients with chronic lung disease or metabolic syndrome without PH. Laser-dissected pulmonary arteries from IPAH and control lungs were tested for the expression of indoleamine-2, 3-dioxygenase (IDO), the rate-limiting enzyme for the conversion from tryptophan to kynurenine. Acute effects of kynurenine were tested in pulmonary vascular preparations, two different models of chronic pulmonary hypertension (PH), and in human pulmonary arterial smooth muscle cells (hPASMCs). In IPAH vs. control serum, kynurenine was significantly elevated (3.6 ± 0.2 vs. 2.6 ± 0.1 µM, < 0.0001), and strongly associated with PH (area under the curve = 0.86), but kynurenine levels were not elevated in lung disease and metabolic syndrome. Among all investigated tryptophan metabolites, kynurenine displayed the strongest correlation with mean pulmonary arterial pressure (mPAP) (ρ: 0.770, < 0.0001). Tryptophan was significantly decreased in IPAH lungs; however, IDO expression was not changed. In hPASMCs, kynurenine increased both cAMP and cGMP; in intrapulmonary arteries, it relaxed the preconstriction via NO/cGMP and cAMP pathways, and in two models of established PH, it acutely decreased the mPAP. Our data suggest that kynurenine elevation might be specifically associated with mPAP; kynurenine acts on hPASMCs in synergy with NO and exerts acute pulmonary vasodilatation in chronic PH models. Kynurenine might provide both a new biomarker and a new therapeutic option for PH.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Accordingly, they found elevated kynurenine levels in a patient cohort consisting of PAH patients. Another research group showed not only elevated kynurenine but also elevated tryptophan levels in PAH (8), while tryptophan in the study by Lewis et al (9) was not associated with pulmonary hypertension.…”

mentioning

confidence: 90%

Importance of kynurenine in pulmonary hypertension

Nagy

Nagaraj

Meinitzer

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…In a recent clinical observation, AA/KYN ratio was decreased in patients with pulmonary arterial hypertension compared with controls. 47 These data suggest that AA can represent the adaptive mechanisms to counteract the changes occurring during hypertension.…”

Section: Discussionmentioning

confidence: 98%

The activation of the kynurenine pathway in a rat model with renovascular hypertension

Bartosiewicz

Kamiński

Pawlak

et al. 2017

Exp Biol Med (Maywood)

Self Cite

View full text Add to dashboard Cite

Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the mechanisms underlying this phenomenon are unclear, our experiment showed a link between renovascular hypertension and activation of kynurenine pathway. Impact statement As hypertension is a major health problem, our research has focused on the connection between the kynurenine pathway and hypertension. We assessed the levels of the main metabolites of dietary tryptophan and analyzed its levels in terms of high blood pressure. The results of our work indicated that in the renovascular rat's model of hypertension, an alteration of the kynurenine pathway occurred. According to our knowledge, this is the first study that has investigated in a comprehensive manner the alteration of the kynurenine pathway under the condition of elevated blood pressure. On the one hand, the work supports a better understanding of pathophysiological basics of the occurrence of hypertension, and on the other hand it provides potential opportunities to treat this disease.

show abstract

“…This effect may also relate to the functional similarity of IDO to nitric oxide synthase (NOS) and its vasorelaxing properties (78). A more recent study (79) evokes another function of this enzyme, which is to promote tryptophan metabolism and alter the activity of the kynurenine pathway. In this clinical evaluation of 26 patients with PAH, kynurenine concentrations and the kynurenine-to-tryptophan ratio correlated positively with the inducible Treg/Th17 and inversely with Th17 subsets.…”

Section: The Translational Gapmentioning

confidence: 99%