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Cardiovascular Research Advance Access originally published online on December 12, 2007
Cardiovascular Research 2008 77(3):443-444; doi:10.1093/cvr/cvm104
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Hypoxia-inducible factor 1{alpha}: a new piece in the preconditioning puzzle

Kirsti Ytrehus*

Department of Medical Physiology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, 9037 Tromso, Norway

* Corresponding author. Tel: +47 77 644 781; fax: +47 77 645 440. E-mail address: Kirsti.ytrehus{at}fagmed.uit.no

Ischaemic preconditioning has proved to be a unique tool for revealing the role of intracellular signal transduction in cell survival of ischaemic heart muscle.1 Downey and co-workers proposed the existence of a sequence of events involving a trigger, mediators, and end effect(s) that are able to delay the progression of cell death.2 By using pharmacological preconditioning protocols, a set of cell membrane receptors that stimulate cell survival signalling have been identified, and use of specific kinase inhibitors has enabled further identification of the key signalling pathways.3,4 With the development of transgenic mice models, a new set of tools for investigation of mechanisms controlling the progression of cell death in the heart are available.

True ischaemic preconditioning, or endogenous preconditioning, involves ischaemia or hypoxia as a triggering factor, but it has taken almost 20 years to see a clear coupling to intracellular oxygen sensors.5 Starting with the idea that cells in the heart muscle, when subjected to transient ischaemia, release a factor that is important for cardioprotection, the role of adenosine was revealed. Also, bradykinin and opioid peptides play a role as paracrine or autocrine signals in protection by ischaemic preconditioning. Addition of scavengers of reactive oxygen species (ROS) with access to the intracellular compartment (like the lipid-soluble antioxidant N-(2-mercaptoproprionyl)glycine (MPG)) blocks ischaemic preconditioning when given prior to and during a preconditioning stimulus, indicating that ROS that are released during short cycles of ischaemia-reperfusion are involved in stimulating protection by preconditioning.

Hypoxia-inducible factor 1 (HIF-1) was discovered in 1992 as a biological oxygen sensor enabling an aerobic organism to adapt to hypoxia by a change in gene expression.5 The HIF-1{alpha} subunit is oxygen labile (containing an oxygen-dependent degradation domain between residues 401 and 603). HIF-1{alpha} is degraded by the proteasome following prolyl-hydroxylation and ubiquitination in normoxic cells. As a result, the level of HIF-1{alpha} will increase in heart tissue when oxygen tension is decreased, and dimerization with constitutively present HIF-1β to form the active HIF-1 complex occurs. An important function for HIF-1 is to increase the transcription of genes for several proteins that promote blood flow and inflammation, including vascular endothelial growth factor, haeme oxygenase-1, endothelial and inducible nitric oxide synthase and cyclooxygenase-2. The full pattern of genes, proteins, and signalling pathways controlled by HIF-1 in the heart remains to be determined. Pharmacological blockade of the HIF-1 complex is proposed to be beneficial to prevent tumour angiogenesis and tumour growth, whereas HIF-1 activation is regarded desirable in ischaemia of the heart and brain.

In the paper, in the current issue of Cardiovascular Research by Cai et al.,1 a role for HIF-1{alpha} in acute endogenous preconditioning against infarction is proposed. Three interesting findings are reported. First, HIF-1{alpha} is either directly or indirectly involved by its function as a regulator of the expression of selected genes responsible for ischaemic preconditioning. Secondly, ischaemia-reperfusion-induced ROS and HIF-1{alpha} (or a protein controlled by HIF-1{alpha}) appear tightly coupled to each other in the heart. Thirdly, the level of oxidized PTEN (the dual lipid and protein tyrosine phosphatase called phosphatase and tensin homologue deleted on chromosome 10) after ischaemia-reperfusion correlates with reduction of infarct size. The study was based on the use of isolated, buffer-perfused hearts from transgenic mice that were heterozygous for HIF-1{alpha}. A homozygote knockout of HIF1{alpha} is reported to be lethal; thus, these hearts were not lacking HIF-1{alpha} completely, but the ability to increase tissue level of the protein during hypoxia was assumed to be markedly reduced (although this was not measured in the present paper).1,6 Importantly, infarct size in heterozygote hearts was not different from wild-type littermate hearts after 30 min global ischaemia, but the response to ischaemic preconditioning was lost.

It is known that PTEN is inactivated by ROS and redox-related mechanisms.7 The source of ROS in PTEN inactivation is often claimed to be the NADPH oxidaze complex.8 In the present paper by Cai et al., isolated mitochondria from hearts were harvested after the ischaemic preconditioning stimulus, and the authors were able to measure an increase in ROS levels in wild-type but not the HIF1{alpha} +/– hearts. Results from several studies demonstrate that there is a close positive correlation and probable causal relationship between Akt/PKB maintained in a phosphorylated form at early reperfusion after ischaemic injury and reduction in cell death.9 Budas et al.10 were able to show that hearts from a 3'-phosphoinositide-dependent kinase-1 (PDK1) hypomorphic mutant mice strain could not be protected against ischaemic injury by ischaemic preconditioning. PDK1 phosphorylates Akt/PKB, p70 ribosomal S6 kinase, and protein kinase C among other proteins. With respect to the possible role of ROS in decreasing dephosphorylation of phospho-Akt through oxidation of PTEN, we have previously11,12 demonstrated that low levels of hydrogen peroxide (1-10 µM) given at reperfusion markedly reduce ischaemic injury in two different models of ischaemic injury in isolated buffer-perfused hearts. A role of PTEN inhibition in cardioprotection also provides an explanation for the variability in success with the use of ROS scavengers to limit reperfusion injury. Interestingly, in the current study protection was reinstituted by adenosine. Although ROS was not measured in the adenosine group, the results support the idea that there is a ROS/HIF1{alpha}-dependent and a ROS/HIF1{alpha}-independent way to cardioprotection by preconditioning.

With respect to the role of mitochondria in acute-phase ischaemic preconditioning, other transgenic models have also provided evidence for this. Glycogen synthase kinase-3β (GSK3β) is a constitutively active kinase inhibited by signalling through Akt/PKB. Inhibitors of the enzyme limit infarct size in ischaemia-reperfusion protocols, and cardiomyocytes from GSK3β knockout mice hearts failed to respond with protection against mitochondrial permeability transition when compared with cells from wild-type hearts in protocols mimicking preconditioning.13 Boengler et al.14 and Schulz et al.15 have shown that connexin 43 is present in mitochondria and propose a recruitment of the protein to the mitochondria in preconditioned hearts; correspondingly, they report that Cx43 heterozygote knockout mouse hearts have reduced ability for ischaemic preconditioning. Similarly, hearts from PKC{epsilon} knockout mice were reported not to be protected by preconditioning, and the enzyme is proposed to be part of a mitochondria-related signalling complex.16,17

In parallel with what has been found for ischaemic preconditioning, both the hypoxic and the cytokine-induced activation of HIF-1 involve the phosphatidylinositol-3-kinase and the mitogen-activated protein kinase signalling pathways.18,19 Some of the tested transgenic models indicate even more complexity, one example showing involvement of arachidonic acid metabolites.20,21 Thus, although several intracellular processes responsible for ischaemic preconditioning have been identified in detail, the precise relation between the different pathways leading to increase in cell survival in the ischaemic heart is less well understood. This also includes the sequence of activation, convergence on an endpoint of protection, and reinforcing mechanisms. Ischaemic preconditioning involves cellular memory—the heart is protected for 1–2 h following short lasting episode of ischaemia reperfusion—and the reinforcing mechanisms or positive feedback mechanisms responsible for maintaining a heart in a protected state remain to be described in detail.

Conflict of interest: none declared.


   Notes
 
The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.


   References
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 References
 

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This Article
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