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-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart
1 Environmental Physiology, The Hebrew University, Jerusalem, Israel
2 Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
3 Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
4 National Institute of Aging, Gerontology Research Center, Baltimore, Maryland, USA
* To whom correspondence should be addressed. E-mail: horowitz{at}cc.huji.ac.il.
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-1
activation in mammals as well. Here we characterize the HIF-1 profile and the transcriptional activation of its target genes following AC and following heat-stress (HS) in hearts from non-acclimated (C, 24°C) and AC (34°C, 1 month) rats. We used Western blot and immunohistochemistry to measure HIF-1a levels, and the electrophoretic mobility shift assay (EMSA) and RT-PCR/qRT-PCR to detect the expression of the HIF-1a 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) following AC, HIF-1 protein levels were increased; 2) HS alone induced transient HIF-1upregulation; and 3) VEGF and HO1 mRNA levels increased following 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 following HS or ischemia. Hearts from AC rats were dramatically protected against infarction following ischemia-perfusion. We conclude that HIF-1 contributes to the acclimation-ischemia cross-tolerance mechanism in the heart by the induction of both chronic and inducible adaptive components.
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