Intermittent hypoxia protects cardiomyocytes against ischemia-reperfusion injury-induced alterations in Ca2+ homeostasis and contraction via the sarcoplasmic reticulum and Na+/Ca2+ exchange mechanisms |
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Authors: | Chen Le Lu Xi-Yuan Li Jun Fu Ji-Dong Zhou Zhao-Nian Yang Huang-Tian |
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Affiliation: | Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, 225 Chong Qing Nan Rd., #1 Bldg., Shanghai 200025, China. |
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Abstract: | We have previously demonstrated that intermittent high-altitude (IHA) hypoxia significantly attenuates ischemia-reperfusion (I/R) injury-induced excessive increase in resting intracellular Ca2+ concentrations ([Ca2+]i). Because the sarcoplasmic reticulum (SR) and Na+/Ca2+ exchanger (NCX) play crucial roles in regulating [Ca2+]i and both are dysfunctional during I/R, we tested the hypothesis that IHA hypoxia may prevent I/R-induced Ca2+ overload by maintaining Ca2+ homeostasis via SR and NCX mechanisms. We thus determined the dynamics of Ca2+ transients and cell shortening during preischemia and I/R injury in ventricular cardiomyocytes from normoxic and IHA hypoxic rats. IHA hypoxia did not affect the preischemic dynamics of Ca2+ transients and cell shortening, but it significantly suppressed the I/R-induced increase in resting [Ca2+]i levels and attenuated the depression of the Ca2+ transients and cell shortening during reperfusion. Moreover, IHA hypoxia significantly attenuated I/R-induced depression of the protein contents of SR Ca2+ release channels and/or ryanodine receptors (RyRs) and SR Ca2+ pump ATPase (SERCA2) and SR Ca2+ release and uptake. In addition, a delayed decay rate time constant of Ca2+ transients and cell shortening of Ca2+ transients observed during ischemia was accompanied by markedly inhibited NCX currents, which were prevented by IHA hypoxia. These findings indicate that IHA hypoxia may preserve Ca2+ homeostasis and contraction by preserving RyRs and SERCA2 proteins as well as NCX activity during I/R. intracellular Ca2+ concentration; Ca2+ transients; Ca2+ transporters; myofilament Ca2+ sensitivity |
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