Diabetic vascular complications contribute to the increased morbidity and mortality of diabetic patients. However, the mechanism of diabetic macrovascular complication remains unclear.
Objective: We intend to unleash the role of DNA methylation modification in the pathological process of diabetic macrovascular complication and identify the potential biomarkers that could be beneficial for early intervention.
Methods: We screened for differentially methylated genes by methylated DNA immunoprecipitation chip (MeDIP-chip) in diabetic patients. The validation of MeDIP-chip was performed by methylation-specific PCR (MSP). Furthermore, we investigated the expressions of the aberrantly methylated genes and their functions in the model of diabetic mice.
Results: Serval aberrantly methylated genes have been explored, including phospholipase C beta 1 (PLCB1), cam kinase I delta (CAMK1D), and dopamine receptor D5 (DRD5) which participated in calcium signaling pathway. Meanwhile, vascular endothelial growth factor B (VEGFB), placental growth factor (PLGF), fatty acid transport protein 3 (FATP3), coagulation factor II thrombin receptor (F2R), and fatty acid transport protein 4 (FATP4) which participated in vascular endothelial growth factor receptor (VEGFR) signaling pathway, were also been found. After MSP and gene expression validation in peripheral blood of patients, PLCB1, PLGF, FATP4, and VEGFB were corroborated. Combining with the detection of fatty acid uptake by radionuclide tracing, DNA methylation regulated VEGFR signaling pathway was demonstrated to mediate the lipid deposition in aortas of diabetic mice.
Conclusions: Our study identifies novel biomarkers and therapeutic targets in diabetic macrovascular complications. DNA methylation in VEGFR signaling pathway might play an important role in diabetic macrovascular complications.
Y. Liao: None. L. Chen: None. T. Zeng: None.
National Natural Science Foundation of China