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Review
. 2012 Jul;32(7):1347-61.
doi: 10.1038/jcbfm.2012.28. Epub 2012 Mar 14.

Hypoxia-inducible factor prolyl hydroxylase inhibition: robust new target or another big bust for stroke therapeutics?

Saravanan S Karuppagounder  1 , Rajiv R Ratan
Affiliations
Review

Hypoxia-inducible factor prolyl hydroxylase inhibition: robust new target or another big bust for stroke therapeutics?

Saravanan S Karuppagounder et al. J Cereb Blood Flow Metab. 2012 Jul.

Abstract

A major challenge in developing stroke therapeutics that augment adaptive pathways to stress has been to identify targets that can activate compensatory programs without inducing or adding to the stress of injury. In this regard, hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) are central gatekeepers of posttranscriptional and transcriptional adaptation to hypoxia, oxidative stress, and excitotoxicity. Indeed, some of the known salutary effects of putative 'antioxidant' iron chelators in ischemic and hemorrhagic stroke may derive from their abilities to inhibit this family of iron, 2-oxoglutarate, and oxygen-dependent enzymes. Evidence from a number of laboratories supports the notion that HIF PHD inhibition can improve histological and functional outcomes in ischemic and hemorrhagic stroke models. In this review, we discuss this evidence and highlight important gaps in our understanding that render HIF PHD inhibition a promising but not yet preclinically validated target for protection and repair after stroke.

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Figures

Figure 1
Figure 1
Hypoxia-inducible factor (HIF) prolyl hydroxylation is a major mechanism for modulating HIF stability and activity. Under normoxia, HIF prolyl hydroxylases (PHDs) in the presence of iron (Fe2+) and 2-oxoglutrate (2OG), hydroxylate the proline residues in the oxygen degradation domain (ODD) of HIF-1α (blue color), which recruits the tumor suppressor protein, the von Hippel Lindau protein (pVHL) to bind and initiate the proteolysis of HIF-1α by acting as a recognition component of ubiquitin ligase complex leading to proteosomal degradation. Factor inhibiting HIF (FIH) hydroxylates asparagine residues in the C-terminal transactivation domain (C-TAD) and prevents the interaction of transcriptional coactivators p300/CBP (CREB-binding protein). Under hypoxia, iron insufficiency, or 2OG depletion, HIF PHD's are inhibited, HIF-1α (red color) stabilized, translocates to nucleus and heterodimerizes with constitutively expressed HIF-1β, binds to the hypoxia responsive elements and induces the expression of target genes.
Figure 2
Figure 2
Hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) expression in the mouse brain. Left panel shows representative Nissl staining images in the mouse brain. Middle panel shows the HIF PHDs 1, 2, and 3 gene expression levels in the mouse brain. Right panel show the quantification of region specific expression of HIF PHD1, 2, and 3 in the mouse brain. (Reproduced with permission from Allen Mouse Brain Atlas. Seattle (WA): Allen Institute for Brain Science © 2009. Available from: http://mouse.brain-map.org).
Figure 3
Figure 3
Domain structures for hypoxia-inducible factor prolyl hydroxylases (HIF PHDs) and factor inhibiting HIF (FIH), an asparagine hydroxylase. Schematic diagram of protein domain structures of HIF PHD1, 2, 3, and FIH with functional motifs/sites.
Figure 4
Figure 4
Mechanisms of stroke neuroprotection by iron chelators: ‘old' and ‘new' model. Schematic representation reflects the evolution in our thinking regarding the mechanisms of neuroprotection by iron chelators. In the old model, deferoxamine (DFO) activates adaptive responses to hypoxia via the induction of hypoxia-inducible factor (HIF)-1 and ATF1/CREB, leading to induction of neuroprotective/neurorestorative genes such as enolase, erythropoietin, vascular endothelial growth factor (VEGF), and p21. In the old model, HIF is the focal point of therapeutic efforts. In the new model, DFO inhibits the HIF prolyl hydroxylases (PHDs), and suppresses prodeath genes like Puma, Chop, and Trib3 via modification of RNA polymerase II and activates prosurvival genes such as Catalase, SOD, and JMJD6 via activation of HIF-2α. HIF-1α may have a small if not antagonistic role in stroke protection and repair.
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