HIF1 alpha/miR-199a/ADM feedback loop modulates the proliferation of human dermal microvascular endothelial cells (HDMECs) under hypoxic condition

摘要

Hypoxia-inducible factor 1 alpha (HIF1 alpha) plays a protective role in the hypoxia-induced cellular injury. In the present study, we attempted to investigate the role and mechanism of HIF1 alpha in human dermal microvascular endothelial cells (hDMECs), a common-used cell model for researches on the hypoxia-induced injury during skin wounds healing. As revealed by ChIP and online tools prediction and confirmed by luciferase reporter and ChIP assays, HIF1A can bind to the promoter regions of ADM and miR-199a, while miR-199a directly binds to the 3MODIFIER LETTER PRIMEUTR of HIF1A and ADM. Hypoxia stress induces HIF1 alpha and ADM expression while inhibits miR-199a expression. Under hypoxic condition, HIF1 alpha knockdown increases the nucleus translocation of p65 and the release of TNF-alpha and IL-8, inhibits the proliferation and migration, while promotes the cellular permeability in HDMECs upon hypoxic stress, while ADM overexpression and miR-199a inhibition exerted an opposite effect on HDMECs. ADM overexpression or miR-199a inhibition could partially reverse the effect of HIF1A knockdown under hypoxia. In summary, we demonstrate a feedback loop consists of HIF1 alpha, miR-199a, and ADM which protect HDMECs from hypoxia-induced cellular injury by modulating the inflammation response, cell proliferation, migration and permeability in HDMECs.