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

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

  • Diabetes Res Clin Pract. 2023 Nov 15:111014. doi: 10.1016/j.diabres.2023.111014.
Fangfang Zeng 1,  Peng Zhou 2,  Meng Wang 1,  Lijie Xie 1,  Xinmei Huang 1,  Yilin Wang 1,  Jinya Huang 1,  Xiaoqing Shao 1,  Yeping Yang 1,  Wenjuan Liu 1,  Maocheng Gu 2,  Yifei Yu 1,  Fei Sun 3,  Min He 1,  Yiming Li 1,  Zhaoyun Zhang 1,  Wei Gong 1,  Yi Wang 4
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 2 Department of Cardiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200040, China.
  • 3 Department of Endocrinology and Metabolism, Pudong New Area Gongli Hospital, Shanghai, 200135, China.
  • 4 Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, 200040, China. Electronic address: [email protected].
PMID: 37977551 DOI: 10.1016/j.diabres.2023.111014
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.

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.

Keywords

ACMSD; NAD(+); NAM; diabetic cardiomyopathy; endothelial cells.

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