ACMSD mediated de novo NAD biosynthetic impairment in cardiac endothelial cells as a potential therapeutic target for diabetic cardiomyopathy.

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.

METHODS

Mice 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.

RESULTS

NAD 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.

CONCLUSION

In summary, increased expression of ACMSD lead to impaired de novo NAD synthesis in diabetic heart. Inhibition of ACMSD could potentially improve DCM.