Abstract
BackgroundConstant hypoxia (CH) and intermittent hypoxia (IH) occur during several pathological conditions such as asthma and obstructive sleep apnea. Our research is focused on understanding the molecular mechanisms that lead to injury or adaptation to hypoxic stress using Drosophila as a model system. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s) in D. melanogaster after exposure to severe (1% O2) intermittent or constant hypoxia.Methodology/Principal FindingsOur microarray analysis has identified multiple gene families that are up- or down-regulated in response to acute CH or IH. We observed distinct responses to IH and CH in gene expression that varied in the number of genes and type of gene families. We then studied the role of candidate genes (up-or down-regulated) in hypoxia tolerance (adult survival) for longer periods (CH-7 days, IH-10 days) under severe CH or IH. Heat shock proteins up-regulation (specifically Hsp23 and Hsp70) led to a significant increase in adult survival (as compared to controls) of P-element lines during CH. In contrast, during IH treatment the up-regulation of Mdr49 and l(2)08717 genes (P-element lines) provided survival advantage over controls. This suggests that the increased transcript levels following treatment with either paradigm play an important role in tolerance to severe hypoxia. Furthermore, by over-expressing Hsp70 in specific tissues, we found that up-regulation of Hsp70 in heart and brain play critical role in tolerance to CH in flies.Conclusions/SignificanceWe observed that the gene expression response to IH or CH is specific and paradigm-dependent. We have identified several genes Hsp23, Hsp70, CG1600, l(2)08717 and Mdr49 that play an important role in hypoxia tolerance whether it is in CH or IH. These data provide further clues about the mechanisms by which IH or CH lead to cell injury and morbidity or adaptation and survival.
Highlights
Constant or intermittent hypoxia frequently occurs in disease states
Using MAPPFinder in conjunction with GENMAPP, we discovered that there were several gene families that were over-represented in Constant hypoxia (CH) treated flies, such as those involved in the response to unfolded proteins, chitin, lipid, carboxylic acid, amino acid-metabolic processes, and the immune response (Table 1, Figure 1A)
We employed gene expression analysis coupled with the functional studies of the role of specific genes in survival to intermittent hypoxia (IH) or CH in vivo using Drosophila as a model system and made two major observations
Summary
Constant or intermittent hypoxia frequently occurs in disease states. For example, intermittent hypoxia (IH) is associated with obstructive sleep apnea, central hypoventilation syndrome and intermittent vascular occlusion in sickle cell anemia. Whether for IH or CH, various studies, using rodents as animal models have examined experimentally the effects of hypoxia on specific tissues such as heart, brain, and kidneys [1,2,3,4,5]. These studies have demonstrated that the response to low O2 is dependent on intensity and duration of the stimulus and on the paradigm used. Constant hypoxia (CH) and intermittent hypoxia (IH) occur during several pathological conditions such as asthma and obstructive sleep apnea. Our current genome-wide study is designed to investigate gene expression changes and identify protective mechanism(s) in D. melanogaster after exposure to severe (1% O2) intermittent or constant hypoxia
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