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1 Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY, USA
2 Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY, USA
3 Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, KY, USA
* To whom correspondence should be addressed. E-mail: david.gozal{at}louisville.edu.
Episodic hypoxia, a characteristic feature of obstructive sleep apnea, induces cellular changes, and apoptosis in brain regions associated with neurocognitive function. To investigate whether mild intermittent hypoxia induces more extensive neuronal damage than a similar sustained hypoxia, PC-12 neuronal cells were subjected to either sustained (5 % O2) or intermittent (alternating 5 % O2 -35 min / 21 % O2 - 25 min) hypoxia, for 2 or 4 days. Quantitative assessment of apoptosis showed that while mild sustained hypoxia did not significantly increase cell apoptosis at 2 days (1.31 ± 0.29 fold; p=NS, n=8), a significant increase in apoptosis occurred after 4 days (2.25 ± 0.4 fold; p<0.002, n=8), without increased caspase activation. Furthermore, caspase inhibition with the general caspase inhibitor, Z-VAD FMK, did not modify sustained hypoxia-induced apoptosis. In contrast, mild intermittent hypoxia induced significant increases in apoptosis at 2 days (3.72 ± 1.43 fold; p<0.03, n=8) and at 4 days (4.57 ± 0.82 fold; p<0.001, n=8), associated with enhanced caspase activity, and attenuated by Z-VAD FMK pretreatment. We conclude that intermittent hypoxia induces an earlier and more extensive apoptotic response that is at least partially dependent on caspase-mediated pathways. In contrast, caspases do not seem to play a role in sustained hypoxia-induced apoptosis. These findings suggest that different signaling pathways are involved in sustained and intermittent hypoxia-induced cell injury, and may contribute to our understanding of differential brain susceptibility to sustained and intermittent hypoxia.
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