Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer
Fig 6
Let-7 represses Dicer and AGO1 that both limit miR-15a expression in hypoxia.
(A) Overexpression of AGO1 mRNA by 0.01, 0.04 and 0.08 μM in hypoxia leads to short-term rises in the expression levels of total miR-15a (B) by promoting the association of free form miR-15a with AGO1 to make more miR-15a RISCs. (C) Dicer processing is a limiting step in the production of miR-15a in hypoxia. Introducing both Dicer and AGO1 mRNAs at the beginning of simulation results in elevated miR-15a abundance compared to adding AGO1 mRNA alone. (D) When let-7 no longer inhibits Dicer translation, an overexpression in Dicer mRNA generates a remarkable change in the expression profiles of Dicer with respect to the control situation. With let-7 mediated Dicer silencing, the response of Dicer mRNA overexpression is significantly attenuated. (E) Relative expression of non-translatable VEGF mRNA associated with miR-15a RISC and (F) translatable VEGF mRNA in response to different treatment strategies. Hypoxia causes an initial increase in the binding between VEGF mRNA and miR-15a RISC because of the rapid HIF-1-activated VEGF transcription, but the impact of AGO1 silencing becomes dominated later that, in the long run, miR-15a-bound VEGF is reduced compared to the normoxic level. In hypoxia, enforced let-7 overexpression or AGO1 silencing modestly increases the amount of translatable VEGF, while let-7 antagonists or AGO1 overexpression can remarkably blunt VEGF production.