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Hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1), constitutively upregulated by HA (1 mo, 34\u00b0C), is a crucial transcription factor in this program, although its specific role is as yet unknown. By using a rat HA model, we studied the impact of disrupting HIF-1\u03b1 transcriptional activation [HIF-1\u03b1:HIF-1\u03b2 dimerization blockade by intraperitoneal acriflavine (4 mg\/kg)] on its mitochondrial gene targets [phosphoinositide-dependent kinase-1 (PDK1), LON, and cyclooxygenase 4 (COX4) isoforms] in the HA rat heart. Physiological measures of cardiac HACT were infarct size after ischemia-reperfusion and time to rigor contracture during hypoxia in cardiomyocytes. We show that HACT requires transcriptional activation of HIF-1\u03b1 throughout the course of HA and that this activation is accompanied by two metabolic switches: 1) profound upregulation of PDK1, which reduces pyruvate entry into the mitochondria, consequently increasing glycolytic lactate production; 2) remodeling of the COX4 isoform ratio, inducing hypoxic-tolerant COX4.2 dominance, and 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 heat shock protein-72 concomitantly with disrupted HIF-1\u03b1 dimerization suggests that HIF-1\u03b1 is essential for HACT. The role of a PDK1 metabolic switch is well known in hypoxia acclimation but not in the HA model and its ischemic setting. Remodeling of COX4 isoforms by environmental acclimation is a novel finding. <\/jats:p>","DOI":"10.1152\/ajpregu.00461.2016","type":"journal-article","created":{"date-parts":[[2017,3,8]],"date-time":"2017-03-08T21:10:39Z","timestamp":1489007439000},"page":"R753-R762","source":"Crossref","is-referenced-by-count":16,"title":["Long-term HIF-1\u03b1 transcriptional activation is essential for heat-acclimation-mediated cross tolerance: mitochondrial target genes"],"prefix":"10.1152","volume":"312","author":[{"given":"Rivka","family":"Alexander-Shani","sequence":"first","affiliation":[{"name":"Laboratory of Environmental Physiology, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Mreisat","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Physiology, Faculty of Dental Medicine, The Hebrew University, Jerusalem, 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