Long- but not short-term heat acclimation produces an apoptosis-resistant cardiac phenotype: A lesson from heat stress and ischemic/reperfusion insults

Miri Assayag, Gary Gerstenblith, Michael D. Stern, Michal Horowitz

Research output: Contribution to journalArticle

Abstract

Long-term heat acclimation (AC, 30d/34°C) is a phenotypic adaptation leading to increased thermotolerance during heat stress (HS, 2 h 41°C). AC also renders protection against ischemic/reperfusion (I/R, 30′ global ischemia/40′ reperfusion) insult via cross-tolerance mechanisms. In contrast to the protected AC phenotype, the onset of acclimation (34°C, AC2d) is characterized by cellular perturbations, suggesting increased susceptibility to HS and I/R insults. In this investigation, we tested the hypothesis that apoptosis resistance is part of the AC repertoire and that, at the initial phase of acclimation (AC2d), cytoprotection is impaired. TUNEL staining and caspase 3 levels in HS and I/R insulted hearts affirmed this hypothesis. To examine the role of the mitochondria in life/death decision in AC2d and 30d AC settings vs. control hearts, we studied the Bcl-2 apoptotic cascade and found increased levels of the anti-apoptotic Bcl-XL and decreased levels of the pro-apoptotic death promoter Bad in hearts from AC2d and AC animals. In these groups, cytochrome c (cyt c) was elevated in the mitochondria and remained unchanged in the cytosol. This adaptation was insufficient to negate apoptosis in AC2d rats. At this early acclimation phase (and in controls), increased caspase 8 activity confirmed activation of the extrinsic (Fas ligand) apoptosis pathway. In conclusion, the elevated Bcl-X L/Bad ratio and decreased cyt c leakage to the cytosol are insufficient to protect the heart and interactions with additional cytoprotective pathways involved in acclimation (elevated HSP70, ROS, and sarcolemmal adaptations to abolish extrinsic apoptosis pathways) are required to induce the apoptosis-resistant AC phenotype.

Original languageEnglish (US)
Pages (from-to)651-664
Number of pages14
JournalCell Stress and Chaperones
Volume15
Issue number5
DOIs
StatePublished - Sep 2010

Keywords

  • Apoptosis
  • Heat acclimation-mediated cross-tolerance
  • Heat stress
  • Ischemia/reperfusion
  • Mitochondria

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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