Hypoxic preconditioning facilitates acclimatization to hypobaric hypoxia in rat heart.
OBJECTIVE
Acute systemic hypoxia induces delayed cardioprotection against ischaemia-reperfusion injury in the heart. As cobalt chloride (CoCl₂) is known to elicit hypoxia-like responses, it was hypothesized that this chemical would mimic the preconditioning effect and facilitate acclimatization to hypobaric hypoxia in rat heart.


METHODS
Male Sprague-Dawley rats treated with distilled water or cobalt chloride (12.5 mg Co/kg for 7 days) were exposed to simulated altitude at 7622 m for different time periods (1, 2, 3 and 5 days).


RESULTS
Hypoxic preconditioning with cobalt appreciably attenuated hypobaric hypoxia-induced oxidative damage as observed by a decrease in free radical (reactive oxygen species) generation, oxidation of lipids and proteins. Interestingly, the observed effect was due to increased expression of the antioxidant proteins hemeoxygenase and metallothionein, as no significant change was observed in antioxidant enzyme activity. Hypoxic preconditioning with cobalt increased hypoxia-inducible factor 1α (HIF-1α) expression as well as HIF-1 DNA binding activity, which further resulted in increased expression of HIF-1 regulated genes such as erythropoietin, vascular endothelial growth factor and glucose transporter. A significant decrease was observed in lactate dehydrogenase activity and lactate levels in the heart of preconditioned animals compared with non-preconditioned animals exposed to hypoxia.


CONCLUSIONS
The results showed that hypoxic preconditioning with cobalt induces acclimatization by up-regulation of hemeoxygenase 1 and metallothionein 1 via HIF-1 stabilization.
Defence Institute of Physiology and Allied Sciences, Defence Research and Development Organization, Lucknow Road, Timarpur, Delhi, India.
Mrinalini
M
Singh
Dhananjay
D
Shukla
Pauline
P
Thomas
Saurabh
S
Saxena
Anju
A
Bansal
D000064:Acclimatization; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003035:Cobalt / Q000008:administration & dosage / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D003035:Cobalt; D008668:Metallothionein; D051547:Heme Oxygenase-1; C018021:cobaltous chloride