Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

Figure 2

HIF-1α under normoxic and hypoxic conditions. In the presence of molecular oxygen, 2-oxoglutarate, and Fe²⁺, HIF-1α is hydroxylated on proline 402 and 564 residues located within ODDD (O₂-dependent degradation domain) by prolyl hydroxylase enzymes (PHDs). Hydroxylation results in the binding of the von Hippel-Lindau (VHL) E3 ligase complex, which ubiquitinates HIF-1α, targeting it to proteasomal degradation. The hydroxylation of the asparagine residue prevents CBP/p300 binding to HIF-1α. Under hypoxic conditions, substrates and coactivators of hydroxylation such as O₂, Fe(II), and 2-oxoglutarate become limited, which leads to the attenuation of HIF-1α hydroxylation. HIF-1α accumulates in the cytosol and is subsequently translocated into the nucleus where it dimerises with the HIF-1β subunit. The HIF-1α/β dimer binds to HREs and regulates target gene expression.