Cardiovascular Research Advance Access first published online on October 11, 2007
This version [Corrected Proof] published online on November 2, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm035
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Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partialdeficiency of HIF-1
1 Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Suite 671,733 North Broadway, Baltimore, MD 21205, USA
3 Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore,MD 21205, USA
5 Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
6 Departments of Pediatrics, Oncology, and Radiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
7 Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA
* Corresponding author. Tel: +1 410 955 1619; fax: +1 443 287 5618. E-mail address: gsemenza{at}jhmi.edu
Aims: We investigated whether hypoxia-inducible factor 1
(HIF-1) plays a role in the acute phase of ischaemic preconditioning (IPC).
Methods and results: Hearts from wild-type (WT) mice and mice heterozygous for a null allele at the locus encoding HIF-1 (HET) were subjected to IPC (10-min ischaemia/5 min reperfusion, or two cycles of 5 min ischaemia/5 min reperfusion), followed by 30 min ischaemia and reperfusion. Left ventricular-developed pressure, heart rate, and coronary flow rate were measured continuously. Apoptosis and infarct size were assessed by TUNEL assay, cleaved caspase 3 immunohistochemistry, and triphenyltetrazolium chloride staining. Production of reactive oxygen species (ROS) in isolated cardiac mitochondria was measured by a chemiluminescence assay. The phosphatase and tensin homologue (PTEN) and AKT (protein kinase B) were analysed by immunoblot assay. IPC improved functional recovery and limited infarct size and apoptosis after prolonged ischaemia–reperfusion in WT hearts, but not in HET hearts. Mitochondrial ROS production, PTEN oxidation, and AKT phosphorylation were impaired in HET hearts. WT and HET hearts were protected by adenosine, which acts via an ROS-independent mechanism.
Conclusion: HIF-1 is required for IPC-induced mitochondrial ROS production and myocardial protection against ischaemia–reperfusion injury.
KEYWORDS Hypoxia; Myocardial infarction; Reactive oxygen species
Time for primary review: 33 days
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