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1 Division of Pulmonary & Critical Care Medicine, University of Washington, Seattle, WA, USA; Section of Pulmonary and Critical Care Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
2 Department of Environment and Occupational Health Sciences, Schoo of Public Health and Community Medicine, University of Washington, Seattle, WA, USA
3 Division of Pulmonary & Critical Care Medicine, University of Washington, Seattle, WA, USA
* To whom correspondence should be addressed. E-mail: sagharib{at}u.washington.edu.
Chronic hypoxic pulmonary hypertension is an important clinical disorder causing significant morbidity. Despite recent discoveries, many molecular mechanisms involved in its pathogenesis remain unexplored. We have undertaken a systematic and unbiased approach to gain global insights into this complex process. By combining transcriptional profiling with rigorous statistical methods and cluster analysis, we identified the dominant temporal patterns of gene expression during progression and regression of hypoxic pulmonary hypertension. We next integrated these results with global gene annotation analysis to identify key biological themes involved in the development and resolution of hypoxic pulmonary hypertension and vascular remodeling. This novel approach assigned biological roles to thousands of candidate genes based on their temporal expression profiles and membership in specific biological modules. Our procedure confirmed several molecular pathways and gene products known to be important in hypoxic pulmonary hypertension. Furthermore, we discovered several novel candidates and molecular mechanisms including IQGAP1, decorin, IGFBP3, and lactotransferrin that may play crucial roles in hypoxic pulmonary hypertension and vascular remodeling. Our methodology of integrating transcriptional profiling, cluster analysis and global gene annotation provides new insights into the pathophysiology of pulmonary hypertension and is applicable to other models of human disease.
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