Importance of kynurenine in pulmonary hypertension

Abstract

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.

Sexual Dimorphism of Metabolomic Profile in Arterial Hypertension

“…3) of the male signature, is even diminished in men. Kynurenine is known to be involved in renovascular hypertension 53 and in arterial hypertension and it could exert a protective vasodilatory effect through the NO pathway 54 . Intriguingly, the tryptophan that is the precursor of kynurenine shows inverse variation in women and men with an increased concentration in women, consistent with the elevation of kynurenine, while it is lowered in men.…”

Establishment of the circadian metabolic phenotype strategy in spontaneously hypertensive rats: a dynamic metabolomics study

“…It has been reported that kynurenine serves as a negative feedback regulator in the event of increased vascular pressure. In arteries, kynurenine may cause arterial relaxation mainly via the cAMP pathway, ameliorating the constantly increased wall stress [52]. However, a continuous increase in arterial blood pressure and a decrease in kynurenine expression indicate that the steady state of tryptophan metabolism is destroyed and the feedback loop is out of order, which in turn leads to an increase in blood pressure.…”

Potential Benefits of Tryptophan Metabolism to the Efficacy of Tocilizumab in COVID-19

“…Kyn is also a potent vasodilator of systemic arteries and has been found to be significantly increased in pulmonary arterial hypertension patients. In chronic models of pulmonary arterial hypertension, Kyn exerted acute pulmonary vasodilatation in synergy with nitric oxide (Nagy et al, 2017).…”