Systems analysis of the human pulmonary arterial hypertension lung transcriptome

Robert S. Stearman, Quan M. Bui, Gil Speyer, Adam Handen, Amber R. Cornelius, Brian B. Graham, Seungchan Kim, Elizabeth A. Mickler, Rubin M. Tuder, Stephen Y. Chan, Mark W. Geraci

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery pressure and vascular resistance, typically leading to right heart failure and death. Current therapies improve quality of life of the patients but have a modest effect on long-term survival. Adetailed transcriptomics and systems biology view of thePAHlung is expected to provide new testable hypotheses for exploring novel treatments. We completed transcriptomics analysis of PAH and control lung tissue to develop disease-specific and clinical data/tissue pathology gene expression classifiers from expression datasets. Gene expression data were integrated into pathway analyses. Gene expression microarray data were collected from 58 PAH and 25 control lung tissues. The strength of the dataset and its derived disease classifier was validated using multiple approaches. Pathways and upstream regulators analyses was completed with standard and novel graphical approaches. The PAH lung dataset identified expression patterns specific to PAH subtypes, clinical parameters, and lung pathology variables. Pathway analyses indicate the important global role of TNF and transforming growth factor signaling pathways. In addition, novel upstream regulators and insight into the cellular and innate immune responses driving PAH were identified. Finally, WNT-signaling pathways may be a major determinant underlying the observed sex differences in PAH. This study provides a transcriptional framework for the PAH-diseased lung, supported by previously reported findings, and will be a valuable resource to the PAHresearch community. Our investigation revealed novel potential targets and pathways amenable to further study in a variety of experimental systems.

Original languageEnglish (US)
Pages (from-to)637-649
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume60
Issue number6
DOIs
StatePublished - Jun 2019

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Keywords

  • Bioinformatics
  • Lung transcriptomics
  • Pulmonary arterial hypertension

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Stearman, R. S., Bui, Q. M., Speyer, G., Handen, A., Cornelius, A. R., Graham, B. B., Kim, S., Mickler, E. A., Tuder, R. M., Chan, S. Y., & Geraci, M. W. (2019). Systems analysis of the human pulmonary arterial hypertension lung transcriptome. American journal of respiratory cell and molecular biology, 60(6), 637-649. https://doi.org/10.1165/rcmb.2018-0368OC