Long-term HIF-1α transcriptional activation is essential for heat-acclimation-mediated cross tolerance: Mitochondrial target genes

Rivka Alexander-Shani, Ahmad Mreisat, Elia Smeir, Gary Gerstenblith, Michael D. Stern, Michal Horowitz

Research output: Contribution to journalArticlepeer-review


An important adaptive feature of heat acclimation (AC) is the induction of cross-tolerance against novel stressors (HACT). Reprogramming of gene expression leading to enhanced innate cytoprotective features by attenuating damage and/or enhancing the response of “help” signals, plays a pivotal role. HIF-1α, constitutively upregulated by AC (1mo, 34°C), is a crucial transcription factor in this program, although its specific role is as yet unknown. By using a rat AC model we studied the impact of disrupting HIF-1α transcriptional activation [(HIF-1α:HIF-1β dimerization blockade by Acriflavine (4mg/kg b.wgt, ip)], on its mitochondrial gene targets (PDK1, LON, COX4 isoforms) in the HACT rat heart. Physiological measures of cardiac HACT were infarct size following ischemia/reperfusion and time to rigor contracture during hypoxia in cardiomyocytes. We show that HACT requires transcriptional activation of HIF-1α throughout the course of AC and that this activation is accompanied by two metabolic switches: (i) profound upregulation of PDK1, which reduces pyruvate entry into the mitochondria, consequently increasing glycolytic lactate production; (ii) remodeling of the COX4 isoform ratio, inducing hypoxic-tolerant COX4.2 dominance, optimizing electron transfer and possibly ATP production during the ischemic and hypoxic insults. LON and COX4.2 transcript upregulation accompanied this shift. Loss of HACT despite elevated expression of the cytoprotective protein HSP72 concomitantly with disrupted HIF-1α dimerization suggests that HIF-1α is essential for HACT. The role of a PDK1 metabolic switch is well known in hypoxia acclimation, but not in the AC model and its ischemic setting. Remodeling of COX4 isoforms by environmental acclimation is a novel finding.

Original languageEnglish (US)
Pages (from-to)R753-R762
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number5
StatePublished - May 30 2017


  • Acriflavine
  • COX4 isoforms
  • HIF-1α
  • Heart
  • Heat acclimation-mediated cross tolerance
  • PDK1

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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