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Hypoxia Signaling in the Cardiovascular System | GeneGlobe

Hypoxia Signaling in the Cardiovascular System


Pathway Description

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.