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First published online December 14, 2005
Journal of Experimental Biology 209, v (2006)
Copyright © 2006 The Company of Biologists Limited
doi: 10.1242/jeb.01996
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Outside JEB |
WARM HEARTS PREPARE RATS FOR BEING SHORT OF BREATH
California Polytechnic State University
San Luis Obispo
ltomanek{at}calpoly.edu
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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, 
and ß, which together form the
active transcription factor that binds to DNA. Unlike HIF-1ß, which is
continually present, HIF-1 levels increase in response to low oxygen
levels. To evaluate the chronic response of HIF-1 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-1 levels in their hearts than those acclimated
to 24°C. To measure the acute response of HIF-1 to heat, they
exposed acclimated animals to 41°C for 2 h. They found that HIF-1
levels 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-1
mRNA levels following heat acclimation, suggesting that changes in translation
or degradation are responsible for the higher HIF-1 levels.
HIF-1 is only active if it associates with the ß-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-1ß
antibody that binds to the ß-subunit of the protein; when they analysed
the resulting antibody-protein complex, they found that the -subunits
were also bound to the complex, which meant that they had associated with the
ß-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.
References
Maloyan, A., Eli-Berchoer, L., Semenza, G. L., Gerstenblith, G.,
Stern, M. D. and Horowitz, M. (2005). HIF-1-targeted
pathways are activated by heat acclimation and contribute to
acclimation-ischemic cross-tolerance in the heart. Physiol.
Genomics 23,79
-88.
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