Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function following myocardial infarction through kynurenine Running Title: tryptophan catabolism in myocardial infarction - Archive ouverte HAL Access content directly
Journal Articles Circulation Year : 2020

Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function following myocardial infarction through kynurenine Running Title: tryptophan catabolism in myocardial infarction

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Nada Joe Melhem
  • Function : Author
Mouna Chajadine
  • Function : Author
Ingrid Gomez
  • Function : Author
Kiave-Yune Howangyin
  • Function : Author
Marion Bouvet
  • Function : Author
Camille Knosp
Yanyi Sun
  • Function : Author
Marie Rouanet
  • Function : Author
Ludivine Laurans
  • Function : Author
Olivier Cazorla
Mathilde Lemitre
  • Function : Author
José Vilar
  • Function : Author
Ziad Mallat
  • Function : Author
Alain Tedgui
  • Function : Author
Hafid Ait-Oufella
Jean-Sébastien Hulot
Jacques Callebert
  • Function : Author
Jean-Marie Launay
Jérémy Fauconnier
Jean-Sébastien Silvestre
  • Function : Author

Abstract

Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI) is one of the leading cause of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes one rate-limiting step of L-Tryptophan (Trp) metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI. METHODS: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction. RESULTS: We show that Kynurenine (Kyn) generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not impact cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function, as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo Kyn supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Notably, Kyn precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism. CONCLUSIONS: These data suggest that IDO could constitute a new therapeutic target during acute MI.
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Dates and versions

inserm-03026653 , version 1 (26-11-2020)

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  • HAL Id : inserm-03026653 , version 1

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Nada Joe Melhem, Mouna Chajadine, Ingrid Gomez, Kiave-Yune Howangyin, Marion Bouvet, et al.. Endothelial cell indoleamine 2, 3-dioxygenase 1 alters cardiac function following myocardial infarction through kynurenine Running Title: tryptophan catabolism in myocardial infarction. Circulation, In press. ⟨inserm-03026653⟩
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