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Is Hif‐1α Essential and Sufficient for Heat Acclimation Cross‐Tolerance?

During heat acclimation (AC) HIF‐1α is constitutively elevated in the heart and the brain. HIF‐1α plays a role in cardioprotection and in spontaneous recovery from traumatic brain injury in the AC phenotype via cross‐tolerance mechanisms (HACT). In this study, we aimed to elucidate whether constitutive vs. transient HIF‐1α up‐regulation is an essential component of HACT. Acriflavine, an inhibitor of HIF‐1 transcriptional activation, was administered (IP) either daily during AC (30d, 34ºC) or as a bolus 2h before Ischemic insult. Cardiac infarct size, rigor contraction of isolated cardiomyocytes and levels of HIF‐1 target proteins or mRNA were measured. The HSF1 ‐ HSP72 cytoprotective cascade was also examined. Daily administration of acriflavine abolished protection in the hearts and cardiomyocytes. Bolus administration of acriflavine only slightly interfered with the protected cardiophenotype. Both treatments attenuated [HIF‐1 α]‐[HIF‐1β] dimerization (CIP), abolished PDK1 translation and up‐regulated GLUT1 levels. HSF1, P‐GSK and HSP72 were up‐regulated. To study the effects of HIF‐1 on COX 4.1 and COX 4.2 Complex IV subunit isoforms in the AC heart, mRNA levels of COX4.2 and LON (protease, COX 4.1 regulator) were measured. AC up‐regulated COX 4.2 and decreased LON levels while the daily acriflavine‐treated group demonstrated a reciprocal outcome. Taken together the similarity in the effects of daily and bolus acriflavine administration on PDK1 and GLUT1 levels and the maintenance of cardioprotection in the bolus group suggests that constitutive HIF‐1 inhibition is required to interfere with HACT. High HSP levels did not abolish this effect, further supporting the essential role of HIF‐1α during the course of AC in HACT. Under these conditions, HSP is not an essential component.