An intrinsic tryptophan metabolite acts as pulmonary vasodilator in pulmonary hypertension

Abstract

The tryptophan metabolite kynurenine is associated with pulmonary hypertension (PH) in dyspnea patients and is increased in PH. In addition, it causes dilation in 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 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 IDO, the enzyme responsible for tryptophan‐kynurenine conversion. Acute effects of kynurenine were tested in pulmonary vascular preparations, two different models of chronic PH, and in human pulmonary arterial smooth muscle cells (hPASMC).Among all investigated tryptophan metabolites, the strongest association to PH was found with kynurenine. In IPAH vs. control, kynurenine was significantly elevated (3.6±0.2μM vs. 2.6±0.1μM, p<0.0001), and strongly associated with PH (AUC=0.86), but kynurenine levels were not elevated in lung disease‐ and metabolic syndrome‐patients. Kynurenine displayed strongest correlation with mean pulmonary arterial pressure (mPAP) (ρ:0.770, p<0.0001). Tryptophan was significantly decreased in IPAH however, IDO expression was not changed. In hPASMCs, kynurenine increased both cAMP and cGMP; in the rat and mouse it relaxed preconstricted intrapulmonary arteries; and in two models of established PH it acutely decreased mPAP.Our data suggest that kynurenine elevation might be specifically associated with mPAP; kynurenine increases both cAMP and cGMP in hPASMC and it exerts acute pulmonary vasodilatation. Kynurenine might provide both a new biomarker for PH and a new therapeutic option.