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Intermittent high altitude hypoxia inhibits the opening of mitochondrial permeability transition pores against reperfusion injury
The role of mitochondrial permeability transition pore (MPTP) in the mechanism of intermittent high altitude (IHA) hypoxic adaptation is not understood. Therefore, we study whether the protective effect of IHA hypoxia against ischemia–reperfusion injury is accompanied by inhibition of the MPTP opening. IHA hypoxia significantly improved the functional recovery of Langendorff hearts on reperfusion and limited infarct size. In isolated myocytes, IHA hypoxia significantly improved the recovery of cell length, lowered ischemia–reperfusion-induced [Ca 2+ ]c and [Ca 2+ ]m overloading. Furthermore, IHA hypoxia accelerated [Ca 2+ ]c decline during reperfusion. Opening the MPTP with atractyloside immediately at reperfusion abolished these cardioprotective effects of IHA hypoxia, but had no appreciable influence on those of normoxic hearts. IHA hypoxia prolongs the time taken to induce MPTP opening and the time taken to induce rigor contracture when myocytes are subjected to oxidative stress. The data from isolated mitochondria demonstrated that IHA hypoxia prevented the decrease of ADP/O ratio, the opening of MPTP and the release of cytochromecfrom mitochondria at high Ca 2+ concentrations (100 and 200 µM). Inhibition of MPTP opening in the first few minutes of reperfusion accelerated [Ca 2+ ]c decline and attenuated [Ca 2+ ]c and [Ca 2+ ]m overloading, which contributed to the cardioprotection of IHA hypoxic adaptation. Enhancement of the tolerance of mitochondria against Ca 2+ might underlie the protective mechanism of IHA hypoxia.
Wei-Zhong Zhua, Yan Xie b, Le Chen b, Huang-Tian Yang, Zhao-Nian Zhou
Source: Journal of Molecular and Cellular Cardiology