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Fig. 7. Testing potential anti-angiogenic strategies targeting HIF1 hydroxylation during normoxia and hypoxia. The effect on hydroxylation by addition of ascorbate (A), PHD2 (B), and iron and ascorbate (C) is shown for [O₂]=50 and 100 µM. Initial concentrations of the compounds not shown are default values (Table 1). (D) Effect of doubling ascorbate concentration on HIF1 hydroxylation as a function of iron, at [O₂]=50 µM. For [Fe²⁺]>5 µM, the increase in hydroxylated HIF1 when [Asc]₀ is increased from 1000 to 2000 µM, remains 0.02 µM. For each reaction, t=10 minutes. Model predictions are based on in vitro values. Physiological in vivo concentrations are also variable, although in general lower. Ascorbate concentrations are estimated as 25-50 µM (Knowles et al., 2003); tissue Fe²⁺ levels may be as low as 10^-12 µM (Bullen et al., 1978), whereas intracellular iron complexes are 3-200 µM (Arredondo et al., 1997; Cooper et al., 1996; Hirsila et al., 2005), the fraction that is freely available for binding to PHD2 depends on cell type; absolute in vivo PHD2 concentrations are yet unknown - in cell extracts, they are in the nanomolar range.

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