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Kynurenine is an endothelium-derived relaxing factor produced during inflammation

Nature Medicine volume 16, pages 279–285 (2010)Cite this article

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A Corrigendum to this article was published on 01 May 2010

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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.

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Figure 1: Ido pathway contributes to the regulation of blood pressure in PbA-infected mice.
Figure 2: Ido contributes to the regulation of blood pressure in LPS-induced endotoxemia.
Figure 3: IFN-γ–dependent expression of Ido in endothelial cells and its associated conversion of tryptophan to kynurenine.
Figure 4: The Ido pathway metabolite kynurenine regulates vascular tone.
Figure 5: Kynurenine relaxes blood vessels via the sGC–cGMP–cGMP-dependent protein kinase pathway.
Figure 6: The adenylyl cyclase–cAMP pathway contributes to kynurenine-induced vessel relaxation.

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Change history

  • 06 May 2010

    In the version of this article initially published, the symbol key in Figure 2g,h is incorrect. The correct symbol key is open circles for Ido1–/– and filled circles for WT. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank E. Andriambeloson, K. Choy, M. Finnemore, A. Mitchell and H. Salahifar for assistance and preliminary experiments, J. Whitworth for the suggestion to test the effect of kynurenine on blood pressure in spontaneously hypertensive rats, G. Head for advice on telemetry and B.H. Chong (University of New South Wales) for providing MEG-01 cells. This work was supported by project grants G03S1177 from the Australian National Heart Foundation to R.S., 400992 and 401106 from the National Health & Medical Research Council (NHMRC) of Australia to R.S., DP0987074 from the Australian Research Council to N.H.H. 512469 from the NHMRC to N.H.H. and National Heart Foundation (OS 98S0008) and Australian Research Council (DP0343325) fellowships to P.K.W. R.S. holds an NHMRC Senior Principal Research Fellowship and University of Sydney Medical Foundation and Professorial Research Fellowships.

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Author notes

  1. Hanzhong Liu & Ben J Wu

    Present address: Present addresses: Division of Pulmonary Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA (H.L.) and The Heart Research Institute, Sydney, Australia (B.J.W.).,

Authors and Affiliations

  1. Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Sydney, Australia

    Yutang Wang, Dechaboon Changsirivathanathamrong & Roland Stocker

  2. Centre for Vascular Research, University of New South Wales, Sydney, Australia

    Yutang Wang, Hanzhong Liu, Ben J Wu, Shane R Thomas & Roland Stocker

  3. School of Medical Sciences, University of New South Wales, Sydney, Australia

    Gavin McKenzie

  4. School of Medical Sciences (Pathology) and Bosch Institute, Faculty of Medicine, University of Sydney, Sydney, Australia

    Paul K Witting, Helen J Ball & Nicholas H Hunt

  5. Cardiovascular Research, Bayer HealthCare, Wuppertal, Germany

    Johannes-Peter Stasch

  6. Medicinal Chemistry, Bayer HealthCare, Wuppertal, Germany

    Michael Hahn

  7. School of Medicine and Pharmacology, University of Western Australia, Perth, Australia

    Vimal Kapoor

  8. Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia

    David S Celermajer

  9. Immunotherapy Center, Medical College of Georgia, Augusta, Georgia, USA

    Andrew L Mellor

  10. University of Massachusetts Medical School, Worcester, Massachusetts, USA

    John F Keaney Jr

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Contributions

J.F.K. Jr. and R.S. conceived of the project and performed initial experiments. Y.W., H.L., P.K.W., J.-P.S., D.C., B.J.W., S.R.T., D.S.C., J.F.K. Jr., N.H.H. and R.S. designed experiments and Y.W. performed most of the experiments and analyzed data. H.L. performed most experiments with porcine coronary arteries, G.M. performed immunohistochemistry, P.K.W. and S.R.T. performed experiments with endothelial cells, J.P.S. and M.H. performed experiments with isolated sGC, D.C. performed mouse endotoxemia experiments, B.J.W. performed experiments in spontaneous hypertensive rats, H.J.B. performed malarial infections of mice, V.K. established blood pressure measurements in unconscious rats and mice, and A.L.M generated Ido1-knockout mice. Y.W. and R.S. wrote and prepared the manuscript, with substantial contributions from H.L., J.F.K. Jr. and N.H.H.

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Correspondence to Roland Stocker.

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Wang, Y., Liu, H., McKenzie, G. et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16, 279–285 (2010). https://doi.org/10.1038/nm.2092

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