Organisms that have acclimated to a particular stressor often find that they can cope better with another stressor that they were not exposed to during their acclimation, a phenomenon known as cross-tolerance. For example,when rats acclimate to high temperatures, their hearts step up their rate of ATP production through anaerobic glycolytic pathways, which suggests that the warm-acclimated heart is also able to cope better with stress caused by oxygen depletion. Since oxygen depletion is a leading cause of heart injury, it would be intriguing to find a molecular switch that confers cross-tolerance to reduced oxygen levels in the heat-acclimated mammalian heart. To find one such potential switch, Maloyan and colleagues from The Hebrew University in Jerusalem examined heat-acclimated rat hearts, focusing on the activation of hypoxia-inducible factor 1 (HIF-1), a transcription factor of genes that are expressed during oxygen depletion.

HIF-1 consists of two subunits, α and β, which together form the active transcription factor that binds to DNA. Unlike HIF-1β, which is continually present, HIF-1α levels increase in response to low oxygen levels. To evaluate the chronic response of HIF-1α to heat, Maloyan and colleagues acclimated 3-week-old rats to either 24°C or 34°C for 30 days. They used immunoblot assays to determine that rats acclimated to 34°C had higher HIF-1α levels in their hearts than those acclimated to 24°C. To measure the acute response of HIF-1α to heat, they exposed acclimated animals to 41°C for 2 h. They found that HIF-1αlevels increased in response to an acute heat shock in non-acclimated but not in heat-acclimated rats. But they didn't see an increase in rats' HIF-1αmRNA levels following heat acclimation, suggesting that changes in translation or degradation are responsible for the higher HIF-1α levels.

HIF-1α is only active if it associates with the β-subunit to create the HIF-1 dimer, so the authors set out to prove that heat stress results in the formation of HIF-1 dimers. They used an anti-HIF-1βantibody that binds to the β-subunit of the protein; when they analysed the resulting antibody-protein complex, they found that the α-subunits were also bound to the complex, which meant that they had associated with theβ-subunits. Using this technique, the team showed that chronic as well as acute heat stress increases the dimerization of the protein. They further showed that these HIF-1 dimers are active when present at high levels and bind to a HIF-1 DNA-binding element, which results in the activation of many of the HIF-1 target genes. For example, the team presented evidence that these higher HIF-1 levels stimulate the expression of erythropoietin, a protein that activates the production of red blood cells, which helps the animals cope with lower oxygen levels.

Does this increase in HIF-1 due to heat acclimation translate into greater protection of the heart from the damaging effects of low oxygen levels? The authors evaluated the rats' cross-tolerance to reduced oxygen levels by lowering the perfusion rate of isolated rat hearts by 75%. Sure enough, they found evidence for cross-tolerance; they saw that heat-acclimated rat hearts had smaller patches of injured heart tissue than non-acclimated hearts. They also showed that, like heat acclimation, acute oxygen depletion activates an increase in HIF-1 levels, with similar consequences. This may be the best evidence yet that a warm heart helps animals survive shortness of breath.


Maloyan, A., Eli-Berchoer, L., Semenza, G. L., Gerstenblith, G.,Stern, M. D. and Horowitz, M. (
). HIF-1α-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart.
Physiol. Genomics