Advanced glycation end products accelerate calcification in VSMCs through HIF-1α/PDK4 activation and suppress glucose metabolism

Scientific Reports
Yi ZhuNai-feng Liu

Abstract

Arterial media calcification is associated with diabetes mellitus. Previous studies have shown that advanced glycation end products (AGEs) are responsible for vascular smooth muscle cell (VSMC) calcification, but the underlying mechanisms remain unclear. Hypoxia-inducible factor-1α (HIF-1α), one of the major factors during hypoxia, and pyruvate dehydrogenase kinase 4 (PDK4), an important mitochondrial matrix enzyme in cellular metabolism shift, have been reported in VSMC calcification. The potential link among HIF-1α, PDK4, and AGEs-induced vascular calcification was investigated in this study. We observed that AGEs elevated HIF-1α and PDK4 expression levels in a dose-dependent manner and that maximal stimulation was attained at 24 h. Two important HIF-1α-regulated genes, vascular endothelial growth factor A (VEGFA) and glucose transporter 1 (GLUT-1), were significantly increased after AGEs exposure. Stabilization or nuclear translocation of HIF-1α increased PDK4 expression. PDK4 inhibition attenuated AGEs-induced VSMC calcification, which was evaluated by measuring the calcium content, alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression levels and by Alizarin red S staining. In additi...Continue Reading

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Citations

Apr 17, 2020·International Journal of Molecular Sciences·Sun Joo LeeJae-Han Jeon
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Methods Mentioned

BETA
nuclear translocation
transfection
immunoprecipitation
protein assay

Software Mentioned

GraphPad Prism
GraphPad
Pro Plus
Image
Statistical Package for Social Science ( SPSS )

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