Physiological and molecular evidence of heat acclimation memory: a lesson from thermal responses and ischemic cross-tolerance in the heart

1 Laboratory of Environmental Physiology, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel 4 School of Computer Science and Engineering, The Hebrew University, Jerusalem, Israel 2 Department of Medicine, Cardiology, Johns Hopkins University, Baltimore, Maryland 3 Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland Sporadic findings in humans suggest that reinduction of heat acclimation (AC) after its loss occurs markedly faster than that during the initial AC session. Animal studies substantiated that the underlying acclimatory processes are molecular. Here we test the hypothesis that faster reinduction of AC (ReAC) implicates "molecular memory." In vivo measurements of colonic temperature profiles during heat stress and ex vivo assessment of cross-tolerance to ischemia-reperfusion or anoxia insults in the heart demonstrated that ReAC only needs 2 days vs. the 30 days required for the initial development of AC. Stress gene profiling in the experimental groups highlighted clusters of transcriptionally activated genes (37%), which included heat shock protein (HSP) genes, antiapoptotic genes, and chromatin remodeling genes. Despite a return of the physiological phenotype to its preacclimation state, after a 1 mo deacclimation (DeAC) period, the gene transcripts did not resume their preacclimation levels, suggesting a dichotomy between genotype and phenotype in this system. Individual detection of hsp70 and hsf1 transcripts agreed with these findings. HSP72, HSF1/P-HSF1, and Bcl-xL protein profiles followed the observed dichotomized genomic response. In contrast, HSP90, an essential cytoprotective component mismatched transcriptional activation upon DeAC. The uniform activation of the similarly responding gene clusters upon De-/ReAC implies that reacclimatory phenotypic plasticity is associated with upstream denominators. During AC, DeAC, and ReAC, the maintenance of elevated/phosphorylated HSF1 protein levels and transcriptionally active chromatin remodeling genes implies that chromatin remodeling plays a pivotal role in the transcriptome profile and in preconditioning to rapid cytoprotective acclimatory memory. cellular memory; cytoprotection; stress proteins; deacclimation; reacclimation