Abstract 12588: Identifying Downstream Targets of Bone Morphogenetic Protein Receptor II Relevant to Pulmonary Arterial Hypertension via Inter-study Meta-analysis of DNA Microarrays
Dysfunctional bone morphogenetic protein receptor (BMPR)II-mediated signaling is a well recognized risk factor for the development of pulmonary arterial hypertension (PAH). These patients exhibit a progressive rise in PA pressure, which eventually leads to right ventricular failure and death. Despite years of research we still poorly understand the downstream targets of BMPRII signaling in pulmonary vasculature, especially their relevance to the pathogenesis of PAH. The goal of this study was to identify key genes and processes that are downstream of BMPRII and relevant to PAH pathogenesis by integrating publicly available microarray expression datasets from NCBI's GEO database. We integrated data from six microarray experiments of either idiopathic PAH patient tissue or BMPRII knockout models. Statistical analysis of the data was performed using either the Statistical Analysis of Microarrays method or a t-test. Genes that were significantly dysregulated in at least three out of six microarrays were analyzed using the National Institute of Allergy and Infectious Diseases' DAVID 2008 functional annotation tool to determine enrichment of biological processes, functions, and pathways. Finally, genes significant in at least three of the six datasets and implicated in vascular biology or disease as determined by a literature search were hierarchically clustered using Eisen laboratory's Cluster and TreeView. Our results suggest that this inter-study meta-analysis is a powerful method to validate and extract maximum value from the available PAH gene expression data. In addition to genes known for their significance in PAH our results revealed novel genes involved in cell proliferation, apoptosis, differentiation, structure, and adhesion that are regulated by BMPRII signaling and are also dysregulated in patients with PAH. This study provides novel and valuable insights into the downstream targets of BMPRII signaling which could be important in the pathobiology of PAH and could have implications in the development of novel treatments.
- © 2010 by American Heart Association, Inc.