Kynurenine is an endothelium-derived relaxing factor produced during inflammation

Abstract

Control of blood vessel tone is central to vascular homeostasis. Here, we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (IDO) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei), and experimental induction of endotoxemia, caused endothelial expression of IDO, resulting in decreased plasma tryptophan, increased kynurenine, and hypotension. Pharmacological inhibition of IDO increased blood pressure in systemically inflamed mice, but not in mice deficient for IDO or interferon-γ, which is required for IDO induction. Tryptophan dilated pre-constricted porcine coronary arteries only if active IDO and an intact endothelium were both present. Kynurenine dose-dependently decreased blood pressure in spontaneously hypertensive rats, inhibited contraction of arteries, and relaxed pre-constricted rings endothelium-independently. Arterial relaxation by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways.

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

“…This decrease correlated with higher disease severity as measured by higher levels of PCT Brought to you by | Universitaetsbibliothek Basel Authenticated Download Date | 10/9/17 4:17 PM and CRP, and higher risk scores (qSOFA and PSI). These results are in line with previous research [26][27][28]. The physiopathological mechanism of decreasing TRP during infection and inflammation is a matter of current discussion [29].…”

Extensive Profiling of the Expression of the Indoleamine 2,3-Dioxygenase 1 Protein in Normal and Tumoral Human Tissues

“…The function of IDO1 in endothelial cells is not known. Its metabolite kynurenine has been shown to have vasodilatory properties (42). Thus, vascular-related side effects of pharmacologic IDO1 inhibition are possible.…”

Plasma Indoleamine 2,3-Dioxygenase Concentration is Increased in Hemodialysis Patients and May Contribute to the Pathogenesis of Coronary Heart Disease

“…25 Experimentally kynurenine increases adhesion of leukocytes to vascular endothelium under flow conditions, 17 but it protects endothelium in hyperhomocysteinemia, 26 decreases blood pressure, and relaxes coronary arteries. 27 On the other hand, increased IDO expression in HD patients with CHD could simply be the result of the chronic inflammation that characterizes this population. [20][21][22] Chronic inflammation is also known to contribute to the pathogenesis of atherosclerosis in HD patients.…”