KLF2 mediates the suppressive effect of BDNF on diabetic intimal calcification by inhibiting HK1 induced endothelial-to-mesenchymal transition

Abstract

Diabetic vascular calcification in the arterial intima is closely associated with endothelial-to-mesenchymal transition (EndMT). Glucose metabolism reprogramming is involved in EndMT. Although brain-derived neurotrophic factor (BDNF) and Krüppel-like family of transcription factor 2 (KLF2) play protective roles in the physiological activity of the vascular endothelium, the underlying mechanisms are unclear. Human umbilical vein endothelial cells (HUVECs) were incubated with diabetic osteogenic medium (DOM) to induce EndMT and accelerate osteogenic differentiation. Glycolysis in HUVECs was assessed by monitoring glucose uptake, lactate production, extracellular acidification rate and expression of key glycolytic enzymes. DOM induced EndMT and accelerated osteo-induction in HUVECs, which was alleviated by BDNF/tropomyosin receptor kinase B (TrkB) pathway. Mechanistically, DOM caused hyperactivation of glycolysis in HUVECs and inhibition of the BDNF/TrkB pathway. BDNF preserved KLF2 and downregulated hexokinase 1 (HK1) in HUVECs after DOM treatment. Furthermore, KLF2 interacted with HK1. Increased KLF2 alleviated HK1-mediated glucose metabolism abnormality. HK1 knockdown or a targeted glycolysis inhibitor suppressed EndMT, apoptosis, inflammation and vascular calcification of HUVECs after DOM exposure. This study suggests that KLF2 mediates the suppressive effect of BDNF on diabetic intimal calcification by inhibiting HK1-induced glucose metabolism reprogramming and the EndMT process.