Physiol. Genomics Information on EB 2010
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Physiol. Genomics 36: 24-34, 2008. First published September 30, 2008; doi:10.1152/physiolgenomics.00258.2007
1094-8341/08 $8.00
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Received 2 November 2007; accepted in final form 23 September 2008.
Physiological Genomics 36:24-34 (2008)
1094-8341/08 $8.00 © 2008 American Physiological Society

Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs

Wei Wu 1,2,*, Nilesh B. Dave 2,*, Guoying Yu 1,2, Patrick J. Strollo 2, Elizabeta Kovkarova-Naumovski 1,2, Stefan W. Ryter 2, Stephen R. Reeves 3, Ehab Dayyat 3, Yang Wang 3, Augustine M. K. Choi 2, David Gozal 3 and Naftali Kaminski 1,2

1 Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh, Pittsburgh, Pennsylvania
2 Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
3 Kosair Children's Hospital Research Institute and Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville, Kentucky

The molecular networks underlying the lung response to hypoxia are not fully understood. We employed systems biology approaches to study temporal effects of intermittent or sustained hypoxia on gene expression in rat lungs. We obtained gene expression profiles from rats exposed to intermittent or sustained hypoxia lasting 0–30 days and identified differentially expressed genes, their patterns, biological processes, and regulatory networks critical for lung response to intermittent or sustained hypoxia. We validated selected genes with quantitative real-time PCR. Intermittent and sustained hypoxia induced two distinct sets of genes in rat lungs that displayed different temporal expression patterns. Intermittent hypoxia induced genes mostly involved in ion transport and homeostasis, neurological processes, and steroid hormone receptor activity, while sustained hypoxia induced genes principally participating in immune responses. The intermittent hypoxia-activated network suggested a role for cross talk between estrogen receptor 1 (ESR1) and other key proteins in hypoxic responses. The sustained hypoxia-activated network was indicative of vascular remodeling and pulmonary hypertension. We confirmed the temporal expression changes of 12 genes (including the Esr1 gene and 4 ESR1 target genes) in intermittent hypoxia and 8 genes in sustained hypoxia with quantitative real-time PCR. Conclusions: intermittent and sustained hypoxia induced distinct gene expression patterns in rat lungs. The functional characteristics of genes activated by these two distinct perturbations suggest their roles in the downstream physiological effects of intermittent and sustained hypoxia. Our results demonstrate the discovery potential of applying systems biology approaches to the understanding of mechanisms underlying hypoxic lung response.

temporal gene expression; microarray analysis; hypoxic response; systems biology






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