Hypoxia‐induced endothelial–mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells

Cardiac fibrosis is integral in chronic heart disease, and one of the cellular processes contributing to cardiac fibrosis is endothelial‐to‐mesenchymal transition (End MT ). We recently found that hypoxia efficiently induces human coronary artery endothelial cells ( HCAEC ) to undergo End MT through a hypoxia inducible factor‐1α ( HIF 1α)‐dependent pathway. Promoter hypermethylation of Ras‐Gap‐like protein 1 ( RASAL 1) has also been recently associated with End MT progression and cardiac fibrosis. Our findings suggest that HIF 1α and transforming growth factor ( TGF )/ SMAD signalling pathways synergistically regulate hypoxia‐induced End MT through both DNMT 3a‐mediated hypermethylation of RASAL 1 promoter and direct SNAIL induction. The findings indicate that multiple cascades may be activated simultaneously to mediate hypoxia‐induced End MT .