Azad Priti, Zhou Dan, Russo Erilynn, Haddad Gabriel G
Department of Pediatrics, Section of Respiratory Medicine, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2009;4(4):e5371. doi: 10.1371/journal.pone.0005371. Epub 2009 Apr 29.
Constant 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% O(2)) intermittent or constant hypoxia.
METHODOLOGY/PRINCIPAL FINDINGS: Our 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/SIGNIFICANCE: We 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.
持续性低氧（CH）和间歇性低氧（IH）发生于多种病理状况，如哮喘和阻塞性睡眠呼吸暂停。我们的研究聚焦于利用果蝇作为模型系统，来理解导致低氧应激损伤或适应的分子机制。我们当前的全基因组研究旨在调查黑腹果蝇暴露于严重（1%氧气）间歇性或持续性低氧后的基因表达变化，并确定保护机制。
方法/主要发现：我们的微阵列分析已鉴定出多个因急性CH或IH而上调或下调的基因家族。我们观察到基因表达对IH和CH的不同反应，这些反应在基因数量和基因家族类型上存在差异。然后，我们研究了候选基因（上调或下调）在严重CH或IH下较长时间（CH为7天，IH为10天）的低氧耐受性（成虫存活）中的作用。热休克蛋白上调（特别是Hsp23和Hsp70）导致CH期间P因子品系的成虫存活率（与对照组相比）显著增加。相反，在IH处理期间，Mdr49和l(2)08717基因（P因子品系）的上调赋予了相对于对照组的存活优势。这表明，两种模式处理后转录水平的增加在对严重低氧的耐受性中起重要作用。此外，通过在特定组织中过表达Hsp70，我们发现心脏和大脑中Hsp70的上调在果蝇对CH的耐受性中起关键作用。
结论/意义：我们观察到基因表达对IH或CH的反应是特异性的且依赖于模式。我们已鉴定出几个基因Hsp23、Hsp70、CG16,00、l(2)08717和Mdr49，它们在CH或IH的低氧耐受性中起重要作用。这些数据为IH或CH导致细胞损伤和发病或适应与存活的机制提供了进一步线索。
