Background
Aneurysms are permanent dilation of the arteries, secondary to pathologic changes of arterial walls. They can occur at any site of arteries and may lead to serious outcomes such as rupture and dissection [
1,
2], which are related to high mortality. Abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA) and intracranial aneurysm (ICA) are three common kinds of aneurysms [
3‐
5]. Intriguingly, previous studies have shown the co-occurrences of any two of them [
6‐
10] at different levels. Furthermore, Kim et al. noted the familial association of aortic aneurysm and ICA [
11], indicating the possible common genetic predisposition underlying the aortic and cerebral aneurysm.
Recently, whole-genome linkage studies have identified some genomic loci serving as common genetic risk factors. For example, 4q32-34 and 19q for AAAs and IAs, 3p24-25 and 5q for TAAs and IAs, and 18q11 and 15q21 for all three kinds of aneurysm [
12,
13]. Besides, an increasing number of gene-expression regulators and key genes were identified in different aneurysms [
14‐
16]. With the development of gene sequencing techniques, there are an increasing number of studies focusing on the expression profile of artery aneurysm [
17‐
19]. However, there are no studies focusing on identifying how gene expression profile preserved in these three kinds of aneurysms.
Therefore, three gene expression microarray datasets in the Gene Expression Omnibus (GEO) were included in the present study. Weighted gene co‑expression network analysis (WGCNA) was used to construct a co-expression network, and the highly preserved expression modules with genes were selected. Subsequently, we performed a comprehensive functional enrichment analysis of the selected modules. The protein–protein interaction (PPI) was conducted with the identification of highly connected genes and their targeted miRNAs. In the present study, the in‑depth analysis may increase the knowledge into the pathogenesis of aneurysm, along with key genes and therapeutic targets for the human aneurysm.
Discussion
One of the key features of pathological changes in aneurysm is inflammatory infiltration and enzymatic destruction of the elastic lamellae and extracellular matrix (ECM) proteins [
43]. Plasma Membrane Calcium ATPase 4 (PMCA4) plays a role in transporting calcium from the cytosol to the extracellular and it is also known to be expressed in aortic tissue [
44]. Kinza et al. [
45] have demonstrated that the expression of PMCA4 could be reduced in human primary aortic endothelial cells during inflammation which enhanced the proteins related to ECM remodeling. Especially, another study conducted by Alexander et al. [
46] reported that mitochondrial calcium uptake 2 (Micu2) is an intermitochondrial membrane protein functioning to reduce the amount of calcium coming into the mitochondrial matrix [
47]. They showed that naive Micu2
−/− mice could develop abdominal aortic aneurysms with spontaneous rupture with modest blood pressure elevation and concluded Micu2 is crucial in protecting the abdominal aorta. In our analysis, the term “positive regulation of cytosolic calcium ion concentration” is underlined in our enrichment analysis for the highly conserved modules and also the hub genes. More thorough knowledge of how the potential regulators including PCMA4 and Micu2 take part in the cytosol calcium concentration regulation during artery aneurysm progression will support the development of therapeutic strategies.
Interestingly, the hub genes in MCODE 6 were predicted to participate in the NF-kappa B pathway with tumor necrosis factor (TNF) as a key player. The other three genes are Lymphotoxin-α and -β (LTA and LTB), and TNF receptor-associated factor 3 (TRAF3). LTA, also called TNF-β, is produced by lymphocytes and is involved in various cellular activities such as promoting lymphoid tissue development and inflammatory and immune responses [
48]. In an earlier study conducted by Magne et al. in the human myeloma cell line OH-2., TNF mediates NF-kappa B activation via both TNF receptors, whereas LTA does so only via TNF-R1. Similarly, LTB, together with its receptor, is also a critical role in the immune system development, response and activation of the pro-inflammatory NF-kappa B pathway [
49]. In vascular smooth muscle cells (VSMCs), the LTB receptor has been demonstrated to participate in atherosclerosis protection via artery tertiary lymphoid organs [
50]. A better understanding of the role of lymphotoxin may help to guide the development of a new therapeutic strategy to treat aneurysm.
Various miRNAs have been identified as key regulators that modulate the pathogenesis of aneurysm [
51,
52]. In our results, miR-26b-5p and miR-335-5p were highlighted. Studies have revealed that miR-26b-5p plays a negative regulatory role in the angiogenesis process of hepatocellular carcinoma. Recently, Changwu et al. reported miR‑26b‑5p regulated the transforming growth factor β (TGFβ)/Smad4 signaling pathway to modulate hypoxia‑induced phenotypic switching of VSMCs. On the other hand, harnessing the results of a prior study [
53], Bei et al. [
54] designed a novel device that would determination of the severity of AAA by detecting miRNA-335-5p. However, little is known about the specific regulation network of these two miRNAs in the aneurysm. Our study provides novel insights for future studies that focus on researching how miRNAs take part in aneurysms.
There are some limitations in the present study. Firstly, our results are based on pure public data with unavoidable biases, such as age and gender differences. Additionally, further in-vivo and in-vitro experimental exploration and validation for the identified genes and modules are required.
Conclusions
To conclude, the present study comprehensively identified the highly conservative co-expression modules and hub genes in three kinds of aneurysms. The potential biological function of the modules, hub genes and the miRNA-hub gene interactions may possess important clinical implications for the treatment and diagnosis of aneurysm.
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