HIF-1α-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart

Alina Maloyan, Luba Eli-Berchoer, Gregg L. Semenza, Gary Gerstenblith, Michael D. Stern, Michal Horowitz

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular hypoxic response. We previously showed that HIF-1 activation is essential for heat acclimation (AC) in Caenorhabditis elegans. Metabolic changes in AC rat hearts indicate HIF-1α activation in mammals as well. Here we characterize the HIF-1α profile and the transcriptional activation of its target genes following AC and following heat stress (HS) in hearts from nonacclimated (C; 24°C) and AC (34°C, 1 mo) rats. We used Western blot and immunohistochemistry to measure HIF-1α levels and EMSA and RT-PCR/quantitative RT-PCR to detect expression of the HIF-1α-targeted genes, including vascular endothelial growth factor (Vegf), heme oxygenase-1 (HO1), erythropoietin (Epo), and Epo receptor (EpoR). EpoR and Epo mRNA levels were measured to determine systemic effects in the kidneys and cross-tolerance effects in C and AC ischemic hearts (Langendorff, 75% ischemia, 40 min). The results demonstrated that 1) after AC, HIF-1α protein levels were increased, 2) HS alone induced transient HIF-1α upregulation, and 3) VEGF and HO1 mRNA levels increased after HS, with greater magnitude in the AC hearts. Epo mRNA in AC kidneys and EpoR mRNA in AC hearts were also elevated. In AC hearts, EpoR expression was markedly higher after HS or ischemia. Hearts from AC rats were dramatically protected against infarction after ischemiaperfusion. We conclude that HIF-1 contributes to the acclimation-ischemia cross-tolerance mechanism in the heart by induction of both chronic and inducible adaptive components.

Original languageEnglish (US)
Pages (from-to)79-88
Number of pages10
JournalPhysiological Genomics
Volume23
Issue number1
DOIs
StatePublished - Sep 21 2005

Keywords

  • Erythropoietin
  • Erythropoietin receptor
  • Heat stress
  • Heme oxygenase-1
  • Hypoxia-inducible factor-1α
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Genetics

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