Importance of kynurenine in pulmonary hypertension

The tryptophan metabolite kynurenine is significantly increased in pulmonary arterial hyper-tension (PAH) patients, and it is a potent vasodilator of systemic arteries. Our aim was to in-vestigate 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 meta-bolic syndrome without-PH. Laser-dissected pulmonary arteries from IPAH and control lungs were tested for the expression of 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 PH, and in human pulmonary arterial smooth muscle cells (hPASMCs). In IPAH vs. control serum, 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 ele-vated in lung disease and metabolic syndrome. Among all investigated tryptophan metabo-lites, kynurenine displayed the strongest correlation with mean pulmonary arterial pressure (mPAP) (:0.770, p<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 pre-constriction 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.

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