Kynurenine is an endothelium-derived relaxing factor produced during inflammation

Yutang Wang, Hanzhong Liu, Gavin McKenzie, Paul K. Witting, Johannes Peter Stasch, Michael Hahn, Dechaboon Changsirivathanathamrong, Ben J. Wu, Helen J. Ball, Shane R. Thomas, Vimal Kapoor, David S. Celermajer, Andrew L. Mellor, John F. Keaney, Nicholas H. Hunt, Roland Stocker

Research output: Contribution to journalArticle

225 Citations (Scopus)

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) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-γ, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.

Original languageEnglish (US)
Pages (from-to)279-285
Number of pages7
JournalNature Medicine
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2010

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Kynurenine
Endothelium-Dependent Relaxing Factors
Tryptophan
Inflammation
Blood pressure
Blood Vessels
Blood Pressure
Metabolism
Endothelium
Plasmodium berghei
Endotoxemia
Guanylate Cyclase
Endothelial cells
Blood vessels
Inbred SHR Rats
Hypotension
Interferons
Rats
Coronary Vessels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wang, Y., Liu, H., McKenzie, G., Witting, P. K., Stasch, J. P., Hahn, M., ... Stocker, R. (2010). Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature Medicine, 16(3), 279-285. https://doi.org/10.1038/nm.2092

Kynurenine is an endothelium-derived relaxing factor produced during inflammation. / Wang, Yutang; Liu, Hanzhong; McKenzie, Gavin; Witting, Paul K.; Stasch, Johannes Peter; Hahn, Michael; Changsirivathanathamrong, Dechaboon; Wu, Ben J.; Ball, Helen J.; Thomas, Shane R.; Kapoor, Vimal; Celermajer, David S.; Mellor, Andrew L.; Keaney, John F.; Hunt, Nicholas H.; Stocker, Roland.

In: Nature Medicine, Vol. 16, No. 3, 01.03.2010, p. 279-285.

Research output: Contribution to journalArticle

Wang, Y, Liu, H, McKenzie, G, Witting, PK, Stasch, JP, Hahn, M, Changsirivathanathamrong, D, Wu, BJ, Ball, HJ, Thomas, SR, Kapoor, V, Celermajer, DS, Mellor, AL, Keaney, JF, Hunt, NH & Stocker, R 2010, 'Kynurenine is an endothelium-derived relaxing factor produced during inflammation', Nature Medicine, vol. 16, no. 3, pp. 279-285. https://doi.org/10.1038/nm.2092
Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature Medicine. 2010 Mar 1;16(3):279-285. https://doi.org/10.1038/nm.2092
Wang, Yutang ; Liu, Hanzhong ; McKenzie, Gavin ; Witting, Paul K. ; Stasch, Johannes Peter ; Hahn, Michael ; Changsirivathanathamrong, Dechaboon ; Wu, Ben J. ; Ball, Helen J. ; Thomas, Shane R. ; Kapoor, Vimal ; Celermajer, David S. ; Mellor, Andrew L. ; Keaney, John F. ; Hunt, Nicholas H. ; Stocker, Roland. / Kynurenine is an endothelium-derived relaxing factor produced during inflammation. In: Nature Medicine. 2010 ; Vol. 16, No. 3. pp. 279-285.
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