Gene regulatory network analysis of perivascular adipose tissue of abdominal aortic aneurysm identifies master regulators of key pathogenetic pathways

Research output: Contribution to journalArticlepeer-review

Abstract

The lack of medical therapy to treat abdominal aortic aneurysm (AAA) stems from our inadequate understanding of the mechanisms underlying AAA pathogenesis. To date, the only available treatment option relies on surgical intervention, which aims to prevent AAA rupture. Identifying specific regulators of pivotal pathogenetic mechanisms would allow the development of novel treatments. With this work, we sought to identify regulatory factors associated with co-expressed genes characterizing the diseased perivascular adipose tissue (PVAT) of AAA patients, which is crucially involved in AAA pathogenesis. We applied a reverse engineering approach to identify cis-regulatory elements of diseased PVAT genes, the associated transcription factors, and upstream regulators. Finally, by analyzing the topological properties of the reconstructed regulatory disease network, we prioritized putative targets for AAA interference treatment options. Overall, we identified NFKB1, SPIB, and TBP as the most relevant transcription factors, as well as MAPK1 and GSKB3 protein kinases and RXRA nuclear receptor as key upstream regulators. We showed that these factors could regulate different co-expressed gene subsets in AAA PVAT, specifically associated with both innate and antigen-driven immune response pathways. Inhibition of these factors may represent a novel option for the development of efficient immunomodulatory strategies to treat AAA.

Original languageEnglish
Article number288
JournalBiomedicines
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 2020

Keywords

  • Abdominal aortic aneurysm
  • Gene regulatory network
  • Immune response
  • Inflammation
  • Perivascular adipose tissue
  • Transcription factors
  • Vascular diseases

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Gene regulatory network analysis of perivascular adipose tissue of abdominal aortic aneurysm identifies master regulators of key pathogenetic pathways'. Together they form a unique fingerprint.

Cite this