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Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 11, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm035
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Complete loss of ischemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1{alpha}

Zheqing Caia,b,e, Hua Zhonga,b, Marta Bosch-Marcea,b, Karen Fox-Talbotc, Lei Wangb, Chiming Weib, Michael A. Trushg and Gregg L. Semenzaa,b,e,f,*

a Vascular Program, Institute for Cell Engineering
b McKusick-Nathans Institute of Genetic Medicine
c Department of Pathology
d Department of Surgery
e Department of Medicine
f Departments of Pediatrics, Oncology, and Radiation Oncology The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
g Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States

* Corresponding author: Broadway Research Building, Suite 671, 733 North Broadway, Baltimore, MD 21205, United States; TEL: 1-410-955-1619; FAX: 1-443-287-5618; Email: gsemenza{at}jhmi.edu

Aims: We investigated whether hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) plays a role in the acute phase of ischemic preconditioning (IPC).

Methods: Hearts from wild-type mice (WT) and mice heterozygous for a null allele at the locus encoding HIF-1{alpha} (HET) were subjected to IPC (10-min ischemia/5-min reperfusion or 2 cycles of 5-min ischemia/5-min reperfusion), followed by 30-min ischemia 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. Reactive oxygen species (ROS) production in isolated cardiac mitochondria was measured by a chemiluminescence assay. The phosphatase PTEN and AKT (protein kinase B) were analyzed by immunoblot assay.

Results: IPC improved functional recovery and limited infarct size and apoptosis after prolonged ischemia-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 ischemia-reperfusion injury.

Time for primary review: 33 days


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