Intermittent high altitude hypoxia inhibits 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 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 [Ca2+]c and [Ca2+]m overloading. Furthermore, IHA hypoxia accelerated [Ca2+]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 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 cytochrome c from mitochondria at high Ca2+ concentrations (100 and 200 microM). Inhibition of MPTP opening in the first few minutes of reperfusion accelerated [Ca2+]c decline and attenuated [Ca2+]c and [Ca2+]m overloading, which contributed to the cardioprotection of IHA hypoxic adaptation. Enhancement of the tolerance of mitochondria against Ca2+ might underlie the protective mechanism of IHA hypoxia.
Zhu
Wei-Zhong
WZ
Laboratory of Hypoxic Cardiovascular Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xie
Yan
Y
Chen
Le
L
Yang
Huang-Tian
HT
Zhou
Zhao-Nian
ZN
D000222:Adaptation, Physiological; D000531:Altitude; D000532:Altitude Sickness; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D045304:Cytochromes c / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000502:physiology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
D045304:Cytochromes c; D002118:Calcium