Hypoxia Signaling in the Cardiovascular System

Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1) which is the primary effector in oxygen regulated gene expression. Although HIF-1 is a heterodimer composed of α and β subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1α, which is otherwise rapidly degraded under normoxic conditions.Above a certain threshold level of O2, HIF-1α is hydroxylated at two prolines and an aspargine residue by prolyl 4-hydroxylase (PH) and an asparginyl hydroxylase (also known as Factor inhibiting HIF (FIH). The hydroxylated prolines permit the binding of von Hippel-Lindau tumor suppressor protein (VHL) binding, thereby triggering ubiquitin conjugation and proteasomal degradation of HIF-α. The hydroxylated asparagine prevents HIF-1α binding to CREB binding protein (CBP/p300), thereby inhibiting transcriptional activation. Hydroxylation of the HIF-1α makes it susceptible to degradation. The activities of PH and HIF are blocked at low oxygen tension or hypoxia, resulting in the stabilization of HIF-1α , enabling it to interact with HIF-1β. The heterodimer recruits (CBP/p300) and binds to the HRE in the promoter or enhancer of target proangiogenic genes, thus promoting transcriptional activation.The tumor suppressor p53 also promotes ubiquitination of HIF-1α , mediated by MDM2, another E3 ubiquitin ligase. p53-mediated HIF-1α degradation occurs in normoxia as well as hypoxia. Under normoxic conditions, inhibitor of nuclear factor of kappa B, I kappa B (Iκ B) plays a role in sequestering p53 in the cytoplasm and prevents p53 nuclear translocation. In response to hypoxia however, dissociation of p53/Iκ B complex occurs and p53 translocates to the nucleus. As a tumor suppressor protein, p53 controls cell growth, repairs damaged DNA and mediates apoptosis, thus contributing to stress alleviation.This pathway highlights the signaling events controlled by the local oxygen tension within a cell in the cardiovascular system.