Submitted on September 14, 2007
Accepted on April 15, 2008
Physiological and molecular evidence of heat acclimation memory: A lesson from thermal responses and ischemic cross-tolerance in the heart
Anna Tetievsky1, Omer Cohen2, Luba Eli-Berchoer2, Gary Gerstenblith3, Michael D. Stern4, Ilan Wapinski5, Nir Friedman6, and Michal Horowitz7*
1 Laboratory of Environmental Physiology, The Hebrew University, Jerusalem, Israel
2 Laboratory of Environmental Physiology, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel
3 Department of Medicine, Cardiology, Johns Hopkins University, Baltimore, Maryland, United States
4 Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States
5 School of Computer Science and Engineering, The Hebrew University, Jerusalem, Israel
6 School of Computer Science and Engineering, Hebrew University, Jerusalem, Israel
7 Laboratory of Environmental Physiology, Hadassah Medical School, Jerusalem, Israel; Laboratory of Environmental Physiology, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel
* To whom correspondence should be addressed. E-mail: horowitz{at}cc.huji.ac.il.
Sporadic findings in humans suggest that re-induction 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 re-induction 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 30d 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, anti-apoptotic genes, and chromatin remodeling genes. Despite a return of the physiological phenotype to its pre-acclimation state, after a one-month de-acclimation (DeAC) period, the gene transcripts did not resume their pre-acclimation 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 BCLxl 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/Re-AC implies that re-acclimatory 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.
