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Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and α -hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia

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ABSTRACT

Introduction: Remote ischemic conditioning (RIC) is a maneuver by which short non-lethal ischemic events are applied on distant organs or limbs to reduce ischemia and reperfusion injuries caused by e.g. myocardial infarct. Although intensively investigated, the specific mechanism of this protective phenomenon remains incompletely understood and in particular, knowledge on the role of small metabolites is scarce.

Objectives: In this study, we aimed to study perturbations in the plasma metabolome following RIC and gain insight into metabolic changes by the intervention as well as to identify potential novel cardio-protective metabolites.

Methods: Blood plasma samples from ten healthy males were collected prior to and after RIC and tested for bioactivity in a HL-1 based cellular model of ischemia–reperfusion damage. Following this, the plasma was analyzed using untargeted LC-qTOF-MS and regulated metabolites were identified using univariate and multivariate statistical analysis. Results were finally verified in a second plasma study from the same group of volunteers and by testing a metabolite ester in the HL-1 cell model.

Results: The analysis revealed a moderate impact on the plasma metabolome following RIC. One metabolite, α-hydroxybutyrate (AHB) however, stood out as highly significantly upregulated after RIC. AHB might be a novel and more sensitive plasma-biomarker of transient tissue ischemia than lactate. Importantly, it was also found that a cell permeable AHB precursor protects cardiomyocytes from ischemia–reperfusion damage.

Conclusion: Untargeted metabolomics analysis of plasma following RIC has led to insight into metabolism during RIC and revealed a possible novel metabolite of relevance to ischemic-reperfusion damage.

Electronic supplementary material: The online version of this article (doi:10.1007/s11306-017-1202-2) contains supplementary material, which is available to authorized users.

No MeSH data available.


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Metabolism of α-keto acids during ischemia: Increased formation of NADH and reduced α-keto acids AHB and 2-hydroxy-3-methylbutyrate and concomitantly downregulated NAD+ and propionyl coenzyme A derived propionylcarnitin during ischemia
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Fig3: Metabolism of α-keto acids during ischemia: Increased formation of NADH and reduced α-keto acids AHB and 2-hydroxy-3-methylbutyrate and concomitantly downregulated NAD+ and propionyl coenzyme A derived propionylcarnitin during ischemia

Mentions: Of the plasma metabolites, AHB increased most significantly (p = 0.00001) in the range of 20–25%. The significance level exceeded the other regulated metabolites with orders of magnitude. The increase was verified by independent quantitative analysis. AHB is the NADH mediated reduction product of α-ketobutyrate. During normoxic conditions, AHB is oxidatively decarboxylated by an NAD+ dependent alpha-keto acid dehydrogenase complex to yield propionyl CoA (Lapointe and Olson 1985). As the NADH/NAD+ ratio is increased during hypoxia, due to impaired oxidative phosphorylation, α-ketobutyrate is likely diverted into AHB rather than into propionyl CoA (Fig. 3). This is in accordance with the decreased levels of propionylcarnitine that we have detected in the current study; given acylcarnitine levels reflect acyl CoA levels. Similarly, 2-hydroxy-3-methylbutyrate is the NADH mediated reduction product of α-ketoisovalerate, a catabolic metabolite of valine (Fig. 3) (Walker et al. 1996). Under normoxic conditions valine is ultimately also degraded to propionyl CoA, i.e. hypoxia could also lead to lower levels of this as well as the coupled carnitine metabolite as mentioned above.


Untargeted metabolomics reveals a mild impact of remote ischemic conditioning on the plasma metabolome and α -hydroxybutyrate as a possible cardioprotective factor and biomarker of tissue ischemia
Metabolism of α-keto acids during ischemia: Increased formation of NADH and reduced α-keto acids AHB and 2-hydroxy-3-methylbutyrate and concomitantly downregulated NAD+ and propionyl coenzyme A derived propionylcarnitin during ischemia
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392534&req=5

Fig3: Metabolism of α-keto acids during ischemia: Increased formation of NADH and reduced α-keto acids AHB and 2-hydroxy-3-methylbutyrate and concomitantly downregulated NAD+ and propionyl coenzyme A derived propionylcarnitin during ischemia
Mentions: Of the plasma metabolites, AHB increased most significantly (p = 0.00001) in the range of 20–25%. The significance level exceeded the other regulated metabolites with orders of magnitude. The increase was verified by independent quantitative analysis. AHB is the NADH mediated reduction product of α-ketobutyrate. During normoxic conditions, AHB is oxidatively decarboxylated by an NAD+ dependent alpha-keto acid dehydrogenase complex to yield propionyl CoA (Lapointe and Olson 1985). As the NADH/NAD+ ratio is increased during hypoxia, due to impaired oxidative phosphorylation, α-ketobutyrate is likely diverted into AHB rather than into propionyl CoA (Fig. 3). This is in accordance with the decreased levels of propionylcarnitine that we have detected in the current study; given acylcarnitine levels reflect acyl CoA levels. Similarly, 2-hydroxy-3-methylbutyrate is the NADH mediated reduction product of α-ketoisovalerate, a catabolic metabolite of valine (Fig. 3) (Walker et al. 1996). Under normoxic conditions valine is ultimately also degraded to propionyl CoA, i.e. hypoxia could also lead to lower levels of this as well as the coupled carnitine metabolite as mentioned above.

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Remote ischemic conditioning (RIC) is a maneuver by which short non-lethal ischemic events are applied on distant organs or limbs to reduce ischemia and reperfusion injuries caused by e.g. myocardial infarct. Although intensively investigated, the specific mechanism of this protective phenomenon remains incompletely understood and in particular, knowledge on the role of small metabolites is scarce.

Objectives: In this study, we aimed to study perturbations in the plasma metabolome following RIC and gain insight into metabolic changes by the intervention as well as to identify potential novel cardio-protective metabolites.

Methods: Blood plasma samples from ten healthy males were collected prior to and after RIC and tested for bioactivity in a HL-1 based cellular model of ischemia–reperfusion damage. Following this, the plasma was analyzed using untargeted LC-qTOF-MS and regulated metabolites were identified using univariate and multivariate statistical analysis. Results were finally verified in a second plasma study from the same group of volunteers and by testing a metabolite ester in the HL-1 cell model.

Results: The analysis revealed a moderate impact on the plasma metabolome following RIC. One metabolite, α-hydroxybutyrate (AHB) however, stood out as highly significantly upregulated after RIC. AHB might be a novel and more sensitive plasma-biomarker of transient tissue ischemia than lactate. Importantly, it was also found that a cell permeable AHB precursor protects cardiomyocytes from ischemia–reperfusion damage.

Conclusion: Untargeted metabolomics analysis of plasma following RIC has led to insight into metabolism during RIC and revealed a possible novel metabolite of relevance to ischemic-reperfusion damage.

Electronic supplementary material: The online version of this article (doi:10.1007/s11306-017-1202-2) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus