Glucose Induces DNMT1/IMPDH2-Dependent Metabolic Memory in Endothelial Cells Upon Reprograming Nucleotide Metabolism

Area of Science:

• Endocrinology and Metabolism
• Vascular Biology
• Epigenetics

Background:

• Type 2 diabetes (T2D) is linked to vascular complications due to 'metabolic memory,' a persistent epigenetic reprogramming.
• Understanding the role of DNA methyltransferase (DNMT) isoforms in this process is crucial for addressing diabetic complications.

Purpose of the Study:

• To investigate the role of DNMT isoforms in regulating glucose-induced metabolic memory in endothelial cells.
• To identify the molecular mechanisms linking metabolic memory to vascular dysfunction and diabetic retinopathy (DR).

Main Methods:

• Analysis of DNMT isoform expression, DNA methylation, oxidative stress, and inflammatory mediators in endothelial cells and mouse models.
• Integrated omics (LC-MS, RRBS) to identify metabolic and epigenomic signatures.
• Validation in human subjects with diabetic retinopathy and ex vivo cell culture models.

Main Results:

• High glucose persistently elevated DNMT1 expression, leading to sustained DNA methylation, oxidative stress, and inflammation.
• Metabolic memory was associated with differential methylation of vascular and nucleotide metabolism genes, notably IMPDH2.
• DNMT1 and IMPDH2 were elevated in diabetic tissues and cells, and their inhibition reduced endothelial dysfunction.

Conclusions:

• DNMT1 plays a key role in establishing and maintaining metabolic memory in endothelial cells.
• IMPDH2, regulated by DNMT1, is a critical mediator of vascular dysfunction in diabetic complications, particularly DR.
• Targeting DNMT1 or IMPDH2 may offer therapeutic strategies for diabetic vascular complications.