Abstract
Object: The highly conserved α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) is the key enzyme that regulates the de novo NAD+ synthesis from tryptophan. NAD+ metabolism in diabetic cardiomyopathy (DCM) was not elucidated yet. MethodsMice were assigned to non-diabetic (NDM) group, streptozocin (STZ)-induced diabetic (DM) group, and nicotinamide (NAM) treated (DM+NAM) group. ACMSD mediated NAD+ metabolism were studied both in mice and patients with diabetes. ResultsNAD+ level was significantly lower in the heart of DM mice than that of the NDM group. Supplementation with NAM could partially increased myocardial capillary density and ameliorated myocardial fibrosis by increasing NAD+ level through salvage pathway. Compared with NDM mice, the expression of ACMSD in myocardial endothelial cells of DM mice was significantly increased. It was further confirmed that in endothelial cells, high glucose promoted the expression of ACMSD. Inhibition of ACMSD could increase de novo NAD+ synthesis and improve endothelial cell function by increasing Sirt1 activity. Targeted mass spectrometry analysis indicated increased ACMSD enzyme activity in diabetic patients, higher ACMSD activity increased risk of heart diastolic dysfunction. ConclusionIn summary, increased expression of ACMSD lead to impaired de novo NAD+ synthesis in diabetic heart. Inhibition of ACMSD could potentially improve DCM.
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