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Tryptophane–kynurenine pathway in the remote ischemic conditioning mechanism

Abstract

The actual protective mechanisms underlying cardioprotection with remote ischemic conditioning (RIC) remain unclear. Recent data suggest that RIC induces kynurenine (KYN) and kynurenic acid synthesis, two metabolites derived from tryptophan (TRP), yet a causal relation between TRP pathway and RIC remains to be established. We sought to study the impact of RIC on the levels of TRP and its main metabolites within tissues, and to assess whether blocking kynurenine (KYN) synthesis from TRP would inhibit RIC-induced cardioprotection. In rats exposed to 40-min coronary occlusion and 2-h reperfusion, infarct size was significantly smaller in RIC-treated animals (35.7 ± 3.0% vs. 46.5 ± 2.2%, p = 0.01). This protection was lost in rats that received 1-methyl-tryptophan (1-MT) pretreatment, an inhibitor of KYN synthesis from TRP (infarct size = 46.2 ± 5.0%). Levels of TRP and nine compounds spanning its metabolism through the serotonin and KYN pathways were measured by reversed-phase liquid chromatography–tandem mass spectrometry in the liver, heart, and limb skeletal muscle, either exposed or not to RIC. In the liver, RIC induced a significant increase in xanthurenic acid, nicotinic acid, and TRP. Likewise, RIC increased NAD-dependent deacetylase sirtuin activity in the liver. Pretreatment with 1-MT suppressed the RIC-induced increases in NAD-dependent deacetylase sirtuin activity. Altogether, these findings indicate that RIC mechanism is dependent on TRP–KYN pathway activation.

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Acknowledgements

The authors would like to thank the “Service commun d’animalerie hospitalo-universitaire”, the university hospital’s Joint Animal Care Department, for taking care of the animals.

Funding

Grant from Angers University Hospital (Grant no. AOI2017).

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Correspondence to Delphine Mirebeau-Prunier.

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The authors declare that they have no conflict of interest.

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Bakhta, O., Pascaud, A., Dieu, X. et al. Tryptophane–kynurenine pathway in the remote ischemic conditioning mechanism. Basic Res Cardiol 115, 13 (2020) doi:10.1007/s00395-019-0770-x

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Keywords

  • Remote ischemia reperfusion
  • Myocardial infarction
  • Kynurenine
  • Tryptophan
  • NAD +