KLF4/Ch25h axis activated by metformin suppresses EndoMT in human umbilical vein endothelial cells.

Metformin, an anti-hyperglycemia drug, protected endothelial cells (ECs) from dysfunction while high glucose (HG) caused endothelial dysfunction. Previously, we found that metformin suppressed endothelial-to-mesenchymal transition (EndoMT), a cellular process that promoted endothelial dysfunction. However, the involved mechanism is still unclear. In this study, we found that metformin increased the expression of krüppel-like factor 4 (KLF4) and cholesterol-25-hydroxylase (Ch25h) while HG decreased the expression of KLF4 and Ch25h. In addition, HG promoted EndoMT indicting by the decrease of endothelial maker genes and increase of mesenchymal maker genes. Furthermore, RNA sequence (RNA-seq) data showed that KLF4 suppressed EndoMT. Moreover, we proved that metformin increased Ch25h expression through not only KLF4 but also epigenetic modification including DNA methylation and active histone modification. Lastly, we proved that Ch25h/25 hydroxycholesterol (25 HC)/Liver X receptor α (LXRα) suppressed EndoMT. Altogether, our study demonstrated that KLF4/Ch25h/axis activated by metformin suppressed EndoMT. Therefore, KLF4/Ch25h/axis may be a new potential therapeutic target for endothelial dysfunction diseases. • High glucose promoted endothelial-to-mesenchymal transition (EndoMT). • High glucose suppressed KLF4/Ch25h axis while metformin activated KLF4/Ch25h axis. • Metformin increased Ch25h expression through both KLF4 and epigenetic modification. • KLF4/Ch25h/25 HC pathway suppressed EndoMT. [ABSTRACT FROM AUTHOR]