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Review
. 2015:2015:549412.
doi: 10.1155/2015/549412. Epub 2015 Jun 4.

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

Agnieszka Zimna  1 , Maciej Kurpisz  1
Affiliations
Review

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

Agnieszka Zimna et al. Biomed Res Int. 2015.

Abstract

The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy.

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Figures

Figure 1
Figure 1
Schematic representation of HIF-α gene structures and DNA binding. (a) HIF-1α and HIF-2α contain the following domains: a nuclear localisation domain (NLS), DNA binding and dimerisation domains (bHLH/PAS), oxygen-dependent degradation domain (ODDD), and cofactor interaction and transcriptional activity domains (N-TAD/C-TAD). HIF-3α lacks a C-TAD domain. NLS: nuclear localisation signal; bHLH: basic helix-loop-helix domain; PAS: Per-ARNT-Sim motif; ODDD: oxygen-dependent degradation domain; N-TAD: N-terminal transactivation domain; C-TAD: C-terminal transactivation domain. (b) Dimerisation of HIF-1α with HIF-1β under hypoxic conditions results in the formation of the HIF-1 transcription factor, which binds to hypoxia response elements (HREs) and activates the transcription of O2-dependent genes (according to [134]).
Figure 2
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.
Figure 3
Figure 3
Different strategies in HIF-1α therapies. Depending on the type of disease and the expected therapeutic effect, different approaches are used in HIF-1 therapies: HIF-1 upregulation (ischaemia) to induce angiogenesis or HIF-1 inhibition to attenuate angiogenesis (cancer). DMOG: dimethyloxalylglycine; DFO: 2-OG analogue (N-oxalylglycine); PR39: macrophage-derived peptide; AdHIF-1α and AdHIF-2α: adenoviral vector; AdCA5: adenovirus encoding a constitutively active form of the HIF-1α; BMDAC: bone marrow-derived angiogenic cells; HIF-1α/VP16: DNA-binding and dimerisation domains of HIF-1α fused with the transactivation domain of herpes simplex virus; K14-HIF-1ΔODD: vector encoding O2-independent HIF-1α under the keratin 14 promoter. Silibinin: nontoxic flavonoid; topotecan: chemotherapeutic agent that is a topoisomerase inhibitor; SAHA and FK228: histone deacetylase inhibitors; acriflavine, bortezomib; amphotericin B: anti-HIF drugs.
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