Journal Article

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart

Zhan, Huiwang, Cai, Zheqing, Semenza, Gregg L., Luo, Weibo

2013

Overview

Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.

• Publisher: National Academy of Sciences,NATIONAL ACADEMY OF SCIENCES,National Acad Sciences
• Subject: acriflavine / Acriflavine - pharmacology / alleles / Animals / Antibodies / Aryl Hydrocarbon Receptor Nuclear Translocator - antagonists & inhibitors / Aryl Hydrocarbon Receptor Nuclear Translocator - genetics / Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism / Biological Sciences / Cell Hypoxia / Cell Line / Chromatin / clinical trials / Coronary vessels / Cytokines / Femoral artery / Genes / Heart / Heart attacks / heterozygosity / Hypoxia / hypoxia-inducible factor 1 / Hypoxia-Inducible Factor 1 - antagonists & inhibitors / Hypoxia-Inducible Factor 1 - genetics / Hypoxia-Inducible Factor 1 - metabolism / Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Immunoblotting / interleukin-10 / Interleukin-10 - blood / Interleukin-10 - genetics / Interleukin-10 - metabolism / Ischemia / Ischemic preconditioning / Ischemic Preconditioning, Myocardial - methods / loci / Messenger RNA / Mice / Mice, Knockout / muscles / Myoblasts, Skeletal - cytology / Myoblasts, Skeletal - drug effects / Myoblasts, Skeletal - metabolism / myocardial infarction / Myocardial Infarction - genetics / Myocardial Infarction - metabolism / Myocardial Infarction - prevention & control / Myocardium - metabolism / Myocardium - pathology / myocytes / Phosphorylation / Plasma / precipitin tests / Protein Binding / Proto-Oncogene Proteins c-akt - metabolism / Reperfusion / Reverse Transcriptase Polymerase Chain Reaction / RNA Interference / Rodents / small interfering RNA / transcription (genetics)