Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1α

Zheqing Cai, Hua Zhong, Marta Bosch-Marce, Karen Fox-Talbot, Lei Wang, Chiming Wei, Michael A. Trush, Gregg L. Semenza

Research output: Contribution to journalArticle

Abstract

Aims: We investigated whether hypoxia-inducible factor 1α (HIF-1α) 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-1α (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-1α is required for IPC-induced mitochondrial ROS production and myocardial protection against ischaemia-reperfusion injury.

Original languageEnglish (US)
Pages (from-to)463-470
Number of pages8
JournalCardiovascular research
Volume77
Issue number3
DOIs
StatePublished - Feb 1 2008

Keywords

  • Hypoxia
  • Myocardial infarction
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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