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Background <p>This study aims to elucidate the effect and mechanism of phospholipid transfer protein (PLTP) on vascular dysfunction in DR and explore the molecular mechanism of abnormal PLTP expression based on DNA methylation.</p> Methods <p>Human retinal microvascular endothelial cells (HRMECs) cultured in high glucose (HG) and streptozotocin-treated mice were used as DR models to detect and screen the key genes with abnormal promoter DNA methylation. Single-cell sequencing, tube formation and migration assays were employed to verify the relationship between PLTP and vascular function. Additionally, siRNA and luciferase reporter assay were used to study the key enzymes regulating the DNA methylation of <i>PLTP</i>. Transcriptome sequencing, coimmunoprecipitation and GSK3β inhibitor were utilized to identify and validate the key downstream pathways of PLTP.</p> Results <p>DR models exhibited DNA hypermethylation and decreased expression of <i>PLTP</i>. Abnormal PLTP expression was implicated in vascular dysfunction, and <i>PLTP</i> overexpression reversed HG-induced effects on the migration and tube formation of endothelial cells. The si<i>DNMT3B</i> and luciferase reporter assay indicated that DNMT3B is the primary enzyme affecting abnormal methylation. Interestingly, PLTP promoted the phosphorylation of AKT and GSK3β, indicating that PLTP modulates angiogenesis via the AKT/GSK3β signaling pathway.</p> Conclusions <p>PLTP regulates the proliferation, migration and tube formation of HRMECs, and is involved in maintaining vascular function via the AKT/GSK3β signaling pathway. In HG environment, increased DNMT3B expression upregulates DNA methylation of the <i>PLTP</i> promoter, downregulating PLTP expression and leading to vascular dysfunction in DR.</p> Graphical abstract <p>PLTP promotes the phosphorylation of AKT and GSK3β, leading to the enhancement of endothelial cell proliferation, migration and tube formation, thereby maintaining vascular function. In HG environment, increased DNMT3B expression results in abnormally increased DNA methylation of the PLTP promoter, leading to decreased PLTP expression and subsequent vascular dysfunction.</p>

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DNA hypermethylation of PLTP mediated by DNMT3B aggravates vascular dysfunction in diabetic retinopathy via the AKT/GSK3β signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月17日

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  • Chunyang Cai,
  • Chufeng Gu,
  • Chunren Meng,
  • Yujie Wang,
  • Qingquan Wei,
  • Shuai He,
  • Dongwei Lai,
  • Xingyun Wang,
  • Tengfei Wang,
  • Qinghua Qiu

摘要

Background

This study aims to elucidate the effect and mechanism of phospholipid transfer protein (PLTP) on vascular dysfunction in DR and explore the molecular mechanism of abnormal PLTP expression based on DNA methylation.

Methods

Human retinal microvascular endothelial cells (HRMECs) cultured in high glucose (HG) and streptozotocin-treated mice were used as DR models to detect and screen the key genes with abnormal promoter DNA methylation. Single-cell sequencing, tube formation and migration assays were employed to verify the relationship between PLTP and vascular function. Additionally, siRNA and luciferase reporter assay were used to study the key enzymes regulating the DNA methylation of PLTP. Transcriptome sequencing, coimmunoprecipitation and GSK3β inhibitor were utilized to identify and validate the key downstream pathways of PLTP.

Results

DR models exhibited DNA hypermethylation and decreased expression of PLTP. Abnormal PLTP expression was implicated in vascular dysfunction, and PLTP overexpression reversed HG-induced effects on the migration and tube formation of endothelial cells. The siDNMT3B and luciferase reporter assay indicated that DNMT3B is the primary enzyme affecting abnormal methylation. Interestingly, PLTP promoted the phosphorylation of AKT and GSK3β, indicating that PLTP modulates angiogenesis via the AKT/GSK3β signaling pathway.

Conclusions

PLTP regulates the proliferation, migration and tube formation of HRMECs, and is involved in maintaining vascular function via the AKT/GSK3β signaling pathway. In HG environment, increased DNMT3B expression upregulates DNA methylation of the PLTP promoter, downregulating PLTP expression and leading to vascular dysfunction in DR.

Graphical abstract

PLTP promotes the phosphorylation of AKT and GSK3β, leading to the enhancement of endothelial cell proliferation, migration and tube formation, thereby maintaining vascular function. In HG environment, increased DNMT3B expression results in abnormally increased DNA methylation of the PLTP promoter, leading to decreased PLTP expression and subsequent vascular dysfunction.