TY - JOUR
T1 - Gene regulatory network analysis of perivascular adipose tissue of abdominal aortic aneurysm identifies master regulators of key pathogenetic pathways
AU - Piacentini, Luca
AU - Chiesa, Mattia
AU - Colombo, Gualtiero Ivanoe
N1 - Funding Information:
Funding: This work was supported by the Italian Ministry of Health (Research Projects RC Nos. 2600658, 2627621, and 2631196).
Publisher Copyright:
© 2020 by the authors.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
KW - Abdominal aortic aneurysm
KW - Gene regulatory network
KW - Immune response
KW - Inflammation
KW - Perivascular adipose tissue
KW - Transcription factors
KW - Vascular diseases
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U2 - 10.3390/BIOMEDICINES8080288
DO - 10.3390/BIOMEDICINES8080288
M3 - Article
AN - SCOPUS:85090086103
VL - 8
JO - Biomedicines
JF - Biomedicines
SN - 2227-9059
IS - 8
M1 - 288
ER -