Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha.
OBJECTIVE
We investigated whether hypoxia-inducible factor 1 alpha (HIF-1 alpha) plays a role in the acute phase of ischaemic preconditioning (IPC).


RESULTS
Hearts from wild-type (WT) mice and mice heterozygous for a null allele at the locus encoding HIF-1 alpha (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.


CONCLUSIONS
HIF-1 alpha is required for IPC-induced mitochondrial ROS production and myocardial protection against ischaemia-reperfusion injury.
Cai
Zheqing
Z
Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Zhong
Hua
H
Bosch-Marce
Marta
M
Fox-Talbot
Karen
K
Wang
Lei
L
Wei
Chiming
C
Trush
Michael A
MA
Semenza
Gregg L
GL
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000241:Adenosine