Hyperglycaemia cause vascular inflammation through advanced glycation end products/early growth response-1 axis in gestational diabetes mellitus
Hyperglycaemia during pregnancy is the main reason for developing diabetes mediated vascular complications. Advanced glycation end products (AGEs) are formed due to non-enzymatic glycation of proteins, lipids and nucleic acids during hyperglycaemia. It has the potential to damage vasculature by modifying the substrate or by means of AGEs and receptor of AGE (RAGE) interaction. It has been linked with the pathogenesis of various vascular diseases including coronary heart disease, atherosclerosis, restenosis etc. This study was carried out to investigate the role of AGEs-EGR-1 pathway in gestational diabetes mellitus (GDM) vascular inflammation. Human umbilical vein endothelial cells (HuVECs) isolated from normal glucose tolerant mothers were subjected to various treatments including high glucose, silencing of early growth response (EGR)-1, blockade of protein kinase C (PKC) β, blocking extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and treatment with AGEs and assayed for EGR-1, tissue factor (TF) and soluble intercellular adhesion molecule (sICAM)-1. Similarly, umbilical vein endothelial cells isolated from normal and GDM mothers were assayed for EGR-1, TF, and sICAM-1. There was a significant increase in EGR-1 and TF levels in HuVECs isolated form GDM mother’s umbilical cord and normal HuVECs treated with high glucose condition. This was accompanied by elevated levels of sICAM-1 in high glucose treated cells. Our results revealed AGE-mediated activation of EGR-1 and its downstream genes via PKC βII and ERK1/2 signaling pathway. The present study demonstrated a novel mechanism of AGEs/ PKC βII/ ERK1/2/EGR-1 pathway in inducing vascular inflammation in GDM.
KeywordsEGR-1 Advanced glycation end products (AGEs) Gestational diabetes mellitus (GDM) Vascular inflammation
We would like to thank our project (SB/FT/LS-432/2012) funding agency - Department of Science and Technology India and TRR fund from SASTRA University for supporting this research. We thank all the nursing staff, physician assistants for helping us with the sample collection as well as for providing patient’s clinical details.
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