Tryptophane-kynurenine pathway in the remote ischemic conditioning mechanism.

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.

Cardioprotective Role of Colchicine Against Inflammatory Injury in a Rat Model of Acute Myocardial Infarction.

BACKGROUND: Inflammation plays a crucial role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. A clinical trial has recently reported a smaller infarct size in a cohort of patients with ST-segment elevation myocardial infarction (MI) treated with a short colchicine course. The mechanism underlying colchicine-induced cardioprotection in the early MI phase remains unclear. We hypothesized that a short pretreatment with colchicine could induce acute beneficial effects by protecting the heart against inflammation in myocardial I/R injury. METHODS AND RESULTS: Rats were subjected to 40-minute left anterior descending coronary occlusion, followed by 120-minute reperfusion. Colchicine (0.3 mg/kg) or a vehicle was administered per os 24 hours and immediately before surgery. Infarct size was significantly reduced in the colchicine group (35.6% ± 3.0% vs 46.6% ± 3.3%, P < .05). The beneficial effects of colchicine were associated with an increased systemic interleukin-10 (IL-10) level and decreased cardiac transforming growth factor-ß level. Interleukin-1ß was found to increase in a "time of reperfusion"-dependent manner. Colchicine inhibited messenger RNA expression of caspase-1 and pro-IL-18. Interleukin-1ß injected 10 minutes prior to myocardial ischemia induced greater infarct size (58.0% ± 2.0%, P < .05) as compared to the vehicle. Colchicine combined to IL-1ß injection significantly decreased infarct size (47.1% ± 2.2%, P < .05) as compared to IL-1ß alone, while colchicine alone exhibited a significantly more marked cardioprotective effect than the colchicine-IL-1ß association. CONCLUSION: The cardioprotection induced by a short colchicine pretreatment was associated with an anti-inflammatory effect in the early reperfusion phase in our rat MI model.

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. METHODS AND 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01390129.