Intermittent hypoxia-generated ROS contributes to intracellular zinc regulation that limits ischemia/reperfusion injury in adult rat cardiomyocyte.

Intermittent hypoxia (IH) has been shown to exert cardioprotective effects against ischemia/reperfusion (I/R) injury through the preservation of ion homeostasis. I/R dramatically elevated cytosolic Zn and caused cardiomyocyte death. However, the role of IH exposure in the relationship between Zn regulation and cardioprotection is still unclear. The aim of the present study was to study whether IH exposure could help in intracellular Zn regulation, hence contributing to cardioprotection against I/R injury. Adult rat cardiomyocytes were exposed to IH (5% O, 5% CO and balanced N) for 30 min followed by 30 min of normoxia (21% O, 5% CO and balanced N). Changes in intracellular Zn concentration were determined using a Zn-specific fluorescent dye, FluoZin-3 or RhodZin-3. Fluorescence was monitored under an inverted fluorescent or confocal microscope. The results demonstrated that I/R or 2,2'-dithiodipyridine (DTDP), a reactive disulphide compound, induced Zn release from metallothioneins (MTs), subsequently causing cytosolic Zn overload, which in turn increased intracellular Zn entry into the mitochondria via a Ca uniporter, hence inducing mitochondrial membrane potential loss, and eventually led to cell death. However, the cytosolic Zn overload and cell death caused by I/R or DTDP was significantly reduced by treatment of cardiomyocytes with IH. The findings from this study suggest that IH might exert its cardioprotective effect through reducing the I/R-induced cytosolic Zn overload and cell death in cardiomyocytes.