Metabolic Signature of Remote Ischemic Preconditioning Involving a Cocktail of Amino Acids and Biogenic Amines.
BACKGROUND
Remote ischemic preconditioning (RIPC) is an attractive therapeutic procedure for protecting the heart against ischemia/reperfusion injury. Despite evidence of humoral mediators transported through the circulation playing a critical role, their actual identities so far remain unknown. We sought to identify plasmatic RIPC-induced metabolites that may play a role.


RESULTS
Rat plasma samples from RIPC and control groups were analyzed using a targeted metabolomic approach aimed at measuring 188 metabolites. Principal component analysis and orthogonal partial least-squares discriminant analysis were used to identify the metabolites that discriminated between groups. Plasma samples from 50 patients subjected to RIPC were secondarily explored to confirm the results obtained in rats. Finally, a combination of the metabolites that were significantly increased in both rat and human plasma was injected prior to myocardial ischemia/reperfusion in rats. In the rat samples, 124 molecules were accurately quantified. Six metabolites (ornithine, glycine, kynurenine, spermine, carnosine, and serotonin) were the most significant variables for marked differentiation between the RIPC and control groups. In human plasma, analysis confirmed ornithine decrease and kynurenine and glycine increase following RIPC. Injection of the glycine and kynurenine alone or in combination replicated the protective effects of RIPC seen in rats.


CONCLUSIONS
We have hereby reported significant variations in a cocktail of amino acids and biogenic amines after remote ischemic preconditioning in both rat and human plasma.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01390129.
University of Angers, France Department of Biochemistry and Genetics, University Hospital of Angers, France Laboratory of Neurovascular and Mitochondrial Integrated Biology, National Institute of Medical Research (INSERM) U771, National Centre of Scientific Research (CNRS) UMR 6214, Angers, France.
Juan Manuel
JM
Chao de la Barca
University of Angers, France Laboratory of Cardioprotection, Remodeling, and Thrombosis, Université d'Angers, Angers, France.
Oussama
O
Bakhta
University of Angers, France Laboratory of Cardioprotection, Remodeling, and Thrombosis, Université d'Angers, Angers, France.
Hussein
H
Kalakech
University of Angers, France Department of Biochemistry and Genetics, University Hospital of Angers, France Laboratory of Oxidative Stress and Metabolic Pathologies (SOPAM), National Institute of Medical Research (INSERM) 1063, Angers, France.
Gilles
G
Simard
University of Angers, France Laboratory of Cardioprotection, Remodeling, and Thrombosis, Université d'Angers, Angers, France.
Sophie
S
Tamareille
Laboratory of Cytogenetic and Cellular Biology, University Hospital of Rennes and National Institute of Medical Research (INSERM) U991, Rennes, France.
Véronique
V
Catros
National Institute of Medical Research (INSERM) U942, Paris, France.
Jacques
J
Callebert
Department of Biochemistry and Genetics, University Hospital of Angers, France.
Cédric
C
Gadras
Department of Biochemistry and Genetics, University Hospital of Angers, France.
Lydie
L
Tessier
University of Angers, France Department of Biochemistry and Genetics, University Hospital of Angers, France Laboratory of Neurovascular and Mitochondrial Integrated Biology, National Institute of Medical Research (INSERM) U771, National Centre of Scientific Research (CNRS) UMR 6214, Angers, France.
Pascal
P
Reynier
University of Angers, France Department of Cardiology, University Hospital of Angers, France Laboratory of Cardioprotection, Remodeling, and Thrombosis, Université d'Angers, Angers, France faprunier@chu-angers.fr.
Fabrice
F
Prunier
University of Angers, France Department of Biochemistry and Genetics, University Hospital of Angers, France Laboratory of Neurovascular and Mitochondrial Integrated Biology, National Institute of Medical Research (INSERM) U771, National Centre of Scientific Research (CNRS) UMR 6214, Angers, France.
Delphine
D
Mirebeau-Prunier
amino acids; infarction; ischemia; reperfusion
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