Gene Regulatory Network Analysis of Perivascular Adipose Tissue of Abdominal Aortic Aneurysm Identifies Master Regulators of Key Pathogenetic Pathways

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.

MiR-30c-1-3p Targets Matrix Metalloproteinase 9 Involved into the Rupture of Abdominal Aortic Aneurysms

“…Our KEGG pathway analysis revealed that miR-30c-1-3p targets were enriched in the axonal guidance, thyroid hormone signaling, and MAPK signaling pathways. Indeed, previous studies indicate that the MAPK pathway is the key biochemical mechanism involved in AAA [17]. Furthermore, MMP-9, one of the main mir-30c-1-3p targets, has been reported to contribute to the rupture of AAAs [18], whereas MMP-9 plasma concentrations are positively correlated with the AAA growth rate [19] and AAA rupture [20,21].…”

A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target

“…There is evidence of increased GSK3β phosphorylation in abdominal aortic aneurysms (AAA) (Krishna et al, 2017). GSK3β was also identified as a likely regulator of pathogenic mechanisms from analysis of perivascular adipose tissue of patients with AAA (Piacentini et al, 2020). Here, we demonstrated that GSK3β inhibition was beneficial in our iPSC-derived MFS VSMCs using both multiple SMIs and a genetic approach.…”

Weighted Gene Co-Expression Network Analysis Reveals Key Genes and Potential Drugs in Abdominal Aortic Aneurysm

“…They described that significantly expressed genes were enriched in this GO term [ 41 ]. Another study showed that the mitotic cell cycle was also significantly associated with dilated aortic perivascular adipose tissue [ 16 ]. The most enriched pathway of the blue module in KEGG was fluid shear stress and atherosclerosis.…”

“…Although the inherent pathology of aneurysm is different between mice and humans, it shares some of the important properties of human AAA, like pronounced inflammatory responses and aortic rupture [11][12][13][14][15]. Based on the findings from mouse models and human samples, AAA is currently accepted as an inflammationdriven disease, as many related processes (such as infiltration of macrophages, neutrophils, B cells and T cells, and activation of inflammatory pathways) were found both in humans and mice [16][17][18][19]. Overactivation of the inflammatory response leads to the destruction of aortic media through the release of proteolytic enzymes and the death of vascular smooth muscle cells, which further promote AAA development [20].…”