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

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

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17462-17467
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
StatePublished - Oct 22 2013

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Hypoxia-Inducible Factor 1
Ischemic Preconditioning
Interleukin-10
Muscle Cells
Reperfusion
Acriflavine
Myocardial Infarction
Heart Injuries
Myocardial Reperfusion
Chromatin Immunoprecipitation
Coronary Occlusion
Femoral Artery
Adenoviridae
Constriction
Small Interfering RNA
Genes
Leg
Coronary Vessels
Arm
Ischemia

Keywords

  • Cardiac surgery
  • Cardioprotection
  • Coronary heart disease
  • Myocardial infarction

ASJC Scopus subject areas

  • General

Cite this

Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. / Cai, Zheqing; Luo, Weibo; Zhan, Huiwang; Semenza, Gregg L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 43, 22.10.2013, p. 17462-17467.

Research output: Contribution to journalArticle

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