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

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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https://www.hal.inserm.fr/inserm-03026653
Contributor : Soraya Taleb <>
Submitted on : Thursday, November 26, 2020 - 5:40:06 PM
Last modification on : Saturday, November 28, 2020 - 3:29:48 AM
Long-term archiving on: : Saturday, February 27, 2021 - 8:08:24 PM

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  • HAL Id : inserm-03026653, version 1

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Nada 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, American Heart Association, In press. ⟨inserm-03026653⟩

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