Metabolic Signature of Remote Ischemic Preconditioning Involving a Cocktail of Amino Acids and Biogenic Amines

Abstract

BackgroundRemote 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.Methods and ResultsRat 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.ConclusionsWe have hereby reported significant variations in a cocktail of amino acids and biogenic amines after remote ischemic preconditioning in both rat and human plasma.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01390129.

Remote ischaemic preconditioning: closer to the mechanism?

“…This is superficially surprising given its well-understood role as an oxygen-sensing enzyme as opposed to one with significant roles in metabolic flux. Some support for a role for the kynurenine pathway in the mechanism of RIPC has been provided by studies in humans and rats in which circulating metabolites, including kynurenine and glycine, that demonstrated elevated levels after RIPC were injected prior to myocardial infarction and had a protective effect 32 .…”

Neural mechanisms in remote ischaemic conditioning in the heart and brain: mechanistic and translational aspects

“…Analysis of the concentrations of metabolites in plasma samples of patients subjected to RIC revealed an increase in glycine concentration following RIC [ 23 ]. This is relevant to the current review, as glycine is known to be an inhibitory neurotransmitter in the central nervous system, and specifically, in parasympathetic nuclei [ 22 , 131 , 132 ].…”

“…This is relevant to the current review, as glycine is known to be an inhibitory neurotransmitter in the central nervous system, and specifically, in parasympathetic nuclei [ 22 , 131 , 132 ]. In the above-mentioned study, the injection of glycine mimicked the protective effects of RIC in rats [ 23 ]. García-Dorado’s group demonstrated that glycine exerts cross-species cardioprotection against infarction through glycine receptor activation [ 66 ].…”

Exploring effects of remote ischemic preconditioning in a pig model of hypothermic circulatory arrest

“…At present, there are three theories: the humoural, the neural, and the systemic [15]. The largest body of preclinical data supports the concept of an RIPCinduced factor(s) in the bloodstream that conveys protection from the transiently ischemic limb to the remote organ(s) [16][17][18][19][20][21][22]. Moreover, the preconditioning protection has been shown to be transferable with the plasma, even in cases of cross-species transfer [17,18,23,24] and it appeared to be mediated via a small, unknown hydrophobic factor under 30 kDa [17,25].…”