Bach1 modulates AKT3 transcription to participate in hyperglycaemia‐mediated EndMT in vascular endothelial cells

Abstract

Hyperglycaemia‐mediated endothelial‐to‐mesenchymal transition (EndMT) is involved in the occurrence and progression of cardiovascular complications in diabetic patients. Previous studies reported that AKT serine/threonine kinase 3 (AKT3) and Bric‐a‐brac/Tramtrack/Broad (BTB) and cap'n'collar (CNC) homology 1 (bach1) participates in endothelial injury and epithelial‐to‐mesenchymal transition. In the present study, we proposed that bach1 regulates AKT3 transcription, thus involved in hyperglycaemia‐mediated EndMT in vascular endothelium. Our results indicated that hyperglycaemia/high glucose increased AKT3 expression and induced EndMT in aorta of diabetic rats and hyperglycaemic human umbilical vein endothelial cells (HUVECs). Moreover, inhibition of AKT3 expression reversed high glucose‐mediated EndMT in HUVECs. Further, hyperglycaemia/high glucose augmented bach1 expression in aorta of diabetic rats and hyperglycaemic HUVECs. Furthermore, si‐bach1 countered high glucose‐induced AKT3 expression and EndMT in HUVECs. In addition, the effect of bach1 overexpression is similar to that of high glucose treatment, which was reversed by si‐AKT3. ChIP assays found bach1 enriched in the promoter region of AKT3. Bach1 overexpression augmented AKT3 promoter activity, which lost after specific binding site mutation. Bach1 was involved in hyperglycaemia‐induced EndMT via modulation of AKT3 transcription.

Regulation of BACH1 by hemin improves cardiac function in a mouse model of myocardial infarction

“…This is in keeping with previous data showing BACH1 levels remain elevated during the first 48h post MI in the murine left ventricular myocardium 24 and microarray data from human circulating endothelial cells demonstrating elevated BACH1 expression after MI 25 . Furthermore, other cardiovascular risk factors such as elevated glucose 26 and aging 27 have also been associated with increased BACH1 expression in the mouse aorta and heart respectively. For aging, this was further linked to increased endothelial cell senescence when under oxidative stress 27 .…”

Experimental Models to Study Endothelial to Mesenchymal Transition in Myocardial Fibrosis and Cardiovascular Diseases

“…EndMT models were therefore designed with EC from these different origins and treated with high glucose concentrations in order to mimic hyperglycemia. HUVEC is widely used as a model for diabetes-associated cardiac fibrosis [ 14 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. In particular, Yu et al showed that 24 h treatment with 30 mM glucose resulted in the expression of the mesenchymal markers α-SMA and type I collagen in HUVEC.…”