Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer
Fig 4
HIF-1α level at time zero is the steady state normoxic (21% O2) level. (A) Total HIF-1α expression profiles are highly sensitive to oxygen availability. (B) When PHD2 initial concentration is in excess, an oxygen-dependent, switch-like behavior in the amount of hydroxylated HIF-1α is observed. As simulation span increases, a steep reduction in HIF-1α hydroxylation occurs between 2% to 4% O2. (C) TTP is responsible for the delayed drop (initial overshoot) in the induction of HIF-1α in hypoxia. By increasing the dose of a simulated siRNA that silences TTP expression (assuming siRNA binds TTP mRNA potently with a Kd of 1 nM), the duration of the initial overshoot is lengthened. (D) Varying the rate of HIF-1α import from cytoplasm into nucleus (kforward) affects the overall HIF-1α profile in hypoxia. (E) Larger kforward values of HIF-1α nuclear import result in higher levels of HIF-1 transcription factor complex formed. (F) Smaller kforward values lead to lower total HIF-1α levels in normoxia and in hypoxia, while the majority of induced HIF-1α is located only in the cytoplasm and unable to form transcription complex with HIF-1β. (D-F) Magnitude of kforward is set to 10%, 50%, 200% and 500% of its original value respectively in the comparisons. For each kforward value, steady state levels of all species, after the model is simulated in normoxia for a long time span, are collected and considered a new set of initial conditions.