DS0403 -


Submission summary

Cardiovascular disease (CVD) such as atherosclerosis and acute myocardial infarction (AMI) is the leading cause of mortality worldwide. In particular, AMI is mainly the complication of atherosclerotic plaque rupture or erosion, and coronary artery occlusion by a thrombus.
Inflammatory mechanisms are involved at all stages of disease development. However, no successful anti-inflammatory therapeutic strategy is currently available to limit CVDs and the complications of AMI. These facts force us to search for new targets and consider better strategies for prediction, prevention, and treatment.
Indoleamine 2-3 dioxygenase 1 (IDO) is an enzyme that catalyzes the degradation of the essential amino acid L-tryptophan (Trp) to N-formylkynurenine leading to the generation of several active metabolites, including kynurenine (Kyn), 3-hydroxykynurenine (3-OHKyn), kynurenic acid (Kna) and quinolinic acid. Over the recent years, IDO has been implicated in the pathophysiology of several inflammatory diseases. During inflammation, IDO is up-regulated mostly in dendritic cells and macrophages by proinflammatory stimuli, notably interferon (IFN)-?. IDO exerts its biological effects mainly through the generation of downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells (Tregs).
Our recent work published in Cell Metabolism showed that, in contrast to previous expectations, IDO does not protect but rather promotes the development of atherosclerosis. We showed that IDO activity sustains an immune-stimulatory potential through inhibition of interleukin (IL)-10, a major immune-regulatory and athero-protective cytokine. In human atherosclerotic lesions, we found increased levels of a Kyn-derived metabolite, kynurenic acid (Kna), which were associated with an unstable plaque phenotype. Moreover, Kna blood levels predicted death and recurrent MI in a population of 981 patients admitted for AMI and recruited in the FAST-MI registry. These results are in agreement with other translational studies showing that IDO activity is associated with cardiovascular risk factors and with worse outcome in coronary artery disease (CAD) patients.
In light of these results, our hypothesis is that IDO1 plays an important role in the regulation of the immuno-inflammatory response after ischemic injury and may greatly impact cardiac remodelling after MI.
Our first results using IDO-deficient mice subjected to cardiac ischemic injury suggest a deleterious role of the enzyme in MI. Our project will be the first to investigate the basic mechanisms responsible for that intriguing phenotype, using state-of-the art in vitro and in vivo approaches to tackle the role of IDO and its major downstream metabolites in the disease process. We will also pursue translational studies to determine local (cardiac) and systemic activity of IDO expression/activity and its derived metabolites, and address their relationships with disease severity and cardiovascular risk.
Finally, we will use therapeutic approach through the study of the impact of pharmacological IDO inhibition (using L-1 methyl-tryptophan) as well as inhibition of the enzyme(s) directly involved in the generation of the Kyn-derived metabolite involved in experimental MI. We will examine these effects on the extent of myocardial necrosis and the recovery of heart function in mouse models of MI and ischemia/reperfusion injury. This proposed project will shed new light on the pathogenesis of CVD and will eventually identify new therapeutic targets.

Project coordinator

Madame Soraya TALEB (institut national de la santé et de la recherche médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


institut national de la santé et de la recherche médicale

Help of the ANR 229,104 euros
Beginning and duration of the scientific project: December 2016 - 36 Months

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