Intermittent high altitude hypoxia protects the heart against lethal Ca 2+ overload injury

Abstract

Adaptation to intermittent high altitude (IHA) hypoxia can protect the heart against ischemia-reperfusion injury. In view of the fact that both Ca 2+ paradox and ischemia-reperfusion injury are associated with the intracellular Ca 2+ overload, we tested the hypothesis that IHA hypoxia may protect hearts against Ca 2+ paradox-induced lethal injury if its cardioprotection bases on preventing the development of intracellular Ca 2+ overload. Langendorff-perfused hearts from normoxic and IHA hypoxic rats were subjected to Ca 2+ paradox (5 min of Ca 2+ depletion followed by 30 min of Ca 2+ repletion) and the functional, biochemical and pathological changes were investigated. The Ca 2+ paradox incapacitated the contractility of the normoxic hearts, whereas the IHA hypoxic hearts significantly preserved contractile activity. Furthermore, the normoxic hearts subjected to Ca 2+ paradox exhibited a marked reduction in coronary flow, increase in lactate dehydrogenase release, and severe myocyte damage. In contrast, these changes were significantly prevented in IHA hypoxic hearts. We, then, tested and confirmed our hypothesis that the protective mechanisms are mediated by mitochondria ATP-sensitive potassium channels (mitoK ATP) and Ca 2+/calmodulin-dependent protein kinase II (CaMKII), as the protective effect of IHA hypoxia was abolished by 5-hydroxydecanoate, a selective mitoK ATP blocker, and significantly attenuated by KN-93, a CaMKII inhibitor. In conclusion, our studies offer for the first time that IHA hypoxia confers cardioprotection against the lethal injury of Ca 2+ paradox and give biochemical evidence for the protective mechanism of IHA hypoxia. We propose that researches in this area may lead a preventive regimen against myocardial injury associated with Ca 2+ overload.