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Mild sustained and intermittent hypoxia induce apoptosis in PC-12 cells via different mechanisms

1 Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville; 2 Department of Pharmacology and Toxicology, University of Louisville; and 3 Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, Kentucky Submitted 7 June 2004...

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Published in:American Journal of Physiology: Cell Physiology 2005-03, Vol.288 (3), p.C535-C542
Main Authors: Gozal, Evelyne, Sachleben, L. R., Jr, Rane, M. J, Vega, C, Gozal, D
Format: Article
Language:English
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Summary:1 Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville; 2 Department of Pharmacology and Toxicology, University of Louisville; and 3 Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, Kentucky Submitted 7 June 2004 ; accepted in final form 1 November 2004 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 would induce more extensive neuronal damage than would a similar degree of sustained hypoxia, rat pheochromocytoma PC-12 neuronal cells were subjected to either sustained (5% O 2 ) or intermittent (alternating 5% O 2 35 min, 21% O 2 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, n = 8; P = NS), a significant increase in apoptosis occurred after 4 days (2.25 ± 0.4-fold, n = 8; P < 0.002), without increased caspase activation. Furthermore, caspase inhibition with the general caspase inhibitor N -benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (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, n = 8; P < 0.03) and at 4 days (4.57 ± 0.82-fold, n = 8; P < 0.001) that was 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 than sustained hypoxia and that this response 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 the understanding of differential brain susceptibility to sustained and intermittent hypoxia. episodic hypoxia; neuronal cell death; caspase; hypoxic adaptation Address for reprint requests and other correspondence: E. Gozal, Kosair Children's Hospital Research Institute, 570 South Preston St., Suite 321, Louisville, KY 40202 (E-mail: evelyne.gozal{at}louisville.edu )
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00270.2004