Résumé
Glutamine is the most abundant amino acid in the plasma, and has been shown to exert cardioprotective effects. However, the underlying mechanisms remained unclear, but may include an anaplerotic effect via its metabolic conversion to citric acid cycle (CAC) intermediates or activation of the hexosamine biosynthetic pathway (HBP).
To assess the potential roles of these mechanisms, we evaluated the metabolic effects of a physiologically relevant concentration of glutamine (0.5
mM) in isolated working rat hearts perfused with
13C-labeled substrates with or without 20 M azaserine (an HBP inhibitor) and under restricted supply of carbohydrates (CHO, i.e. without pyruvate/insulin).
When perfused with a mixture of CHOs, a fatty acid oleate and insulin (controls), the addition of glutamine had no effect on functional parameters except for a 17% (p<0.05) decrease in relaxation. However it resulted in an increase in the percent contribution of
13C-oleate to acetyl-CoA production (51%) and triglyceride formation (2.8 folds). This was accompanied by a significant reduction (p>0.05) tissue levels of the CAC intermediates (in nmol/gww): citrate: 260 ± 10
vs. 222 ± 6 and malate 128 ± 5
vs. 103 ± 3. Inhibition of HBP with azaserine restored oleate oxidation and tissue CAC levels, but not triglyceride formation. When perfused under restricted supply of CHOs, hearts displayed significantly decreased cardiac output (65%), a greater percent contribution of glucose to pyruvate formation (60%), and lower tissue citrate and malate levels (45%). Addition of glutamine restored cardiac output and glucose contribution to pyruvate formation but not tissue CAC levels.
Collectively, these results demonstrate the capacity of glutamine to modulate energy substrate selection and function in the perfused heart. Furthermore, the potential mechanisms underlying these effects appear to be mediated via the HBP rather than anaplerosis.