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

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 546
Author(s):  
Ke-Jia Kan ◽  
Feng Guo ◽  
Lei Zhu ◽  
Prama Pallavi ◽  
Martin Sigl ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Network Analysis ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Gene Interaction ◽  
Mitotic Cell ◽  
Aortic Disease ◽  
Pharmaceutical Therapy ◽  
Abdominal Aortic ◽  
Key Genes

Abdominal aortic aneurysm (AAA) is a prevalent aortic disease that causes high mortality due to asymptomatic gradual expansion and sudden rupture. The underlying molecular mechanisms and effective pharmaceutical therapy for preventing AAA progression have not been fully identified. In this study, we identified the key modules and hub genes involved in AAA growth from the GSE17901 dataset in the Gene Expression Omnibus (GEO) database through the weighted gene co-expression network analysis (WGCNA). Key genes were further selected and validated in the mouse dataset (GSE12591) and human datasets (GSE7084, GSE47472, and GSE57691). Finally, we predicted drug candidates targeting key genes using the Drug–Gene Interaction database. Overall, we identified key modules enriched in the mitotic cell cycle, GTPase activity, and several metabolic processes. Seven key genes (CCR5, ADCY5, ADCY3, ACACB, LPIN1, ACSL1, UCP3) related to AAA progression were identified. A total of 35 drugs/compounds targeting the key genes were predicted, which may have the potential to prevent AAA progression.

scholarly journals IKK Epsilon Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Inhibiting Inflammation, Oxidative Stress, and Apoptosis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Hao Chai ◽  
ZhongHao Tao ◽  
YongChao Qi ◽  
HaoYu Qi ◽  
Wen Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Ang Ii ◽  
Elastin Degradation ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Primary Mouse

Abdominal aortic aneurysm (AAA) is a vascular disorder that is considered a chronic inflammatory disease. However, the precise molecular mechanisms involved in AAA have not been fully elucidated. Recently, significant progress has been made in understanding the function and mechanism of action of inhibitor of kappa B kinase epsilon (IKKε) in inflammatory and metabolic diseases. The angiotensin II- (Ang II-) induced or pharmacological inhibitors were established to test the effects of IKKε on AAA in vivo. After mice were continuously stimulated with Ang II for 28 days, morphologically, we found that knockout of IKKε reduced AAA formation and drastically reduced maximal diameter and severity. We also observed a decrease in elastin degradation and medial destruction, which were independent of systolic blood pressure or plasma cholesterol concentrations. Western blot analyses and immunohistochemical staining were carried out to measure IKKε expression in AAA tissues and cell lines. AAA phenotype of mice was measured by ultrasound and biochemical indexes. In zymography, immunohistology staining, immunofluorescence staining, and reactive oxygen species (ROS) analysis, TUNEL assay was used to examine the effects of IKKε on AAA progression in AAA mice. IKKε deficiency significantly inhibited inflammatory macrophage infiltration, matrix metalloproteinase (MMP) activity, ROS production, and vascular smooth muscle cell (VSMC) apoptosis. We used primary mouse aortic VSMC isolated from apolipoprotein E (Apoe) −/− and Apoe−/−IKKε−/− mice. Mechanistically, IKKε deficiency blunted the activation of the ERK1/2 pathway. The IKKε inhibitor, amlexanox, has the same impact in AAA. Our results demonstrate a critical role of IKKε in AAA formation induced by Ang II in Apoe−/− mice. Targeting IKKε may constitute a novel therapeutic strategy to prevent AAA progression.

scholarly journals Eosinophils Protect Mice from Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm

2020 ◽  
Author(s):  
Cong-Lin Liu ◽  
Xin Liu ◽  
Yuanyuan Zhang ◽  
Jing Liu ◽  
Chongzhe Yang ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Aortic Disease ◽  
Immunofluorescent Staining ◽  
Blood Eosinophil ◽  
Cationic Protein ◽  
Abdominal Aortic ◽  
M1 Macrophage

Rationale: Blood eosinophil (EOS) count and EOS cationic protein (ECP) associate with human cardiovascular diseases (CVD). Yet, whether EOS play a role in CVD remains untested. The current study detected EOS accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting EOS participation in this aortic disease. Objective: To test whether and how EOS affect AAA growth. Methods and Results: Population-based randomized clinically controlled screening trials revealed higher blood EOS count in 579 male AAA patients than in 5,063 non-AAA control (0.236{plus minus}0.182 vs 0.211{plus minus}0.154, 109/L, P<0.001). Univariate (OR=1.381, P<0.001) and multivariate (OR=1.237, P=0.031) logistic regression analyses indicated that increased blood EOS count in AAA patients served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected EOS accumulation and EOS cationic protein expression in human and murine AAA lesions. Results showed that EOS deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell (SMC) loss using angiotensin-II perfusion-induced AAA in Apoe -/- and EOS-deficient Apoe -/- ;∆dblGATA mice. EOS deficiency increased lesion chemokine expression, muted lesion expression of IL4 and EOS-associated-ribonuclease-1 (mEar1, human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, EOS-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b + Ly6C lo monocytes. mEar1 treatment or adoptive transfer of EOS from WT and Il13 -/- mice, but not EOS from Il4 -/- mice, blocked AAA growth in Apoe -/- ∆dblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for EOS IL4 and mEar1 in blocking NF-κB activation in macrophages, SMCs, and endothelial cells. Conclusions: EOS play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

scholarly journals Transcriptional profiling and network analysis of the murine angiotensin II-induced abdominal aortic aneurysm

2011 ◽  
Vol 43 (17) ◽  
pp. 993-1003 ◽  
Author(s):  
Joshua M. Spin ◽  
Mark Hsu ◽  
Junya Azuma ◽  
Maureen M. Tedesco ◽  
Alicia Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Network Analysis ◽  
Aortic Aneurysm ◽  
Mapk Signaling ◽  
Aortic Dilatation ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Aneurysm Development

We sought to characterize temporal gene expression changes in the murine angiotensin II (ANG II)-ApoE−/− model of abdominal aortic aneurysm (AAA). Aortic ultrasound measurements were obtained over the 28-day time-course. Harvested suprarenal aortic segments were evaluated with whole genome expression profiling at 7, 14, and 28 days using the Agilent Whole Mouse Genome microarray platform and Statistical Analysis of Microarrays at a false discovery rate of <1%. A group of angiotensin-treated mice experienced contained rupture (CR) within 7 days and were analyzed separately. Progressive aortic dilatation occurred throughout the treatment period. However, the numerous early expression differences between ANG II-treated and control were not sustained over time. Ontologic analysis revealed widespread upregulation of inflammatory, immune, and matrix remodeling genes with ANG II treatment, among other pathways such as apoptosis, cell cycling, angiogenesis, and p53 signaling. CR aneurysms displayed significant decreases in TGF-β/BMP-pathway signaling, MAPK signaling, and ErbB signaling genes vs. non-CR/ANG II-treated samples. We also performed literature-based network analysis, extracting numerous highly interconnected genes associated with aneurysm development such as Spp1, Myd88, Adam17 and Lox. 1) ANG II treatment induces extensive early differential expression changes involving abundant signaling pathways in the suprarenal abdominal aorta, particularly wide-ranging increases in inflammatory genes with aneurysm development. 2) These gene expression changes appear to dissipate with time despite continued growth, suggesting that early changes in gene expression influence disease progression in this AAA model, and that the aortic tissue adapts to prolonged ANG II infusion. 3) Network analysis identified nexus genes that may constitute aneurysm biomarkers or therapeutic targets.

scholarly journals Bioinformatics analysis of potential common molecular pathogenesis assumed by intracranial aneurysm, aortic aneurysm and aortic dissection

2021 ◽  
Author(s):  
Chao Zhao ◽  
Xinchun Cui ◽  
Guodong Liu ◽  
Jianlong Li ◽  
Jinxing Liu ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Intracranial Aneurysm ◽  
Molecular Mechanisms ◽  
Biological Processes ◽  
Network Analyses ◽  
Abdominal Aortic ◽  
Genetic Overlap ◽  
Pathogenesis Related

Abstract This study is intended to find possible pathogenesis-related genetic overlap and common molecular mechanisms of intracranial aneurysm, abdominal aortic aneurysm and aortic dissection. Three mRNA microarray datasets,GSE75436 of intracranial aneurysms, GSE7084 of abdominal aortic aneurysm and GSE52093 of aortic dissection were downloaded from Gene Expression Omnibus and detected in silico . DEGs of these three datasets screened through GEO2R, respectively . The overlapping genes were found by Venny mapping. Subsequently, Gene Ontology, Kyoto Encyclopedia of Genes and Genomespathway enrichment analysiswere performed using the DAVID database and protein-protein interaction network analyses were conducted by STRING and Cytoscape webpage tool to illustrate the molecular mechanisms in their pathogenesis and progression.This study identified 178 DEGs, including SMTN, MYH11, TAGLN, ACTG2, CNN1, MYLK, LMOD1, MYL9,VCL and ACTC1 in the the most significant module. Except for those confirmed biological processes, mesenchyme migration and platelet aggregation are common biological processes shared by genes in the most significant module and the hub genes. Focal adhesionssignaling pathway is highlighted in this analysis. The present study identified possible pathogenesis-related genetic overlap and common molecular mechanisms of intracranial aneurysm, abdominal aortic aneurysm and aortic dissection, which may contribute to their diagnosis, treatment and prognostic prediction with a systematic view.

Identification of potential proteases for abdominal aortic aneurysm by weighted gene coexpression network analysis

Genome ◽  
2020 ◽  
Vol 63 (11) ◽  
pp. 561-575
Author(s):  
Hui Zhang ◽  
Dan Yang ◽  
Siliang Chen ◽  
Fangda Li ◽  
Liqiang Cui ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Network Analysis ◽  
Aortic Aneurysm ◽  
Coexpression Network ◽  
Gene Coexpression Network ◽  
Hub Genes ◽  
Gene Coexpression ◽  
Abdominal Aortic ◽  
T Cell Regulation ◽  
Coexpression Network Analysis

Proteases are involved in the degradation of the extracellular matrix (ECM), which contributes to the formation of abdominal aortic aneurysm (AAA). To identify new disease targets in addition to the results of previous microarray studies, we performed next-generation sequencing (NGS) of the whole transcriptome of Angiotensin II-treated ApoE−/− male mice (n = 4) and control mice (n = 4) to obtain differentially expressed genes (DEGs). Identified DEGs of proteases were analyzed using weighted gene coexpression network analysis (WGCNA). RT-qPCR was conducted to validate the differential expression of selected hub genes. We found that 43 DEGs were correlated with the expression of the protease profile, and most were clustered in immune response module. Among 26 hub genes, we found that Mmp16 and Mmp17 were significantly downregulated in AAA mice, while Ctsa, Ctsc, and Ctsw were upregulated. Our functional annotation analysis of genes coexpressed with the five hub genes indicated that Ctsw and Mmp17 were involved in T cell regulation and Cell adhesion molecule pathway, respectively, and that both were involved in general regulation of the cell cycle and gene expression. Overall, our data suggest that these ectopic genes are potentially crucial to AAA formation and may act as biomarkers for the diagnosis of AAA.

scholarly journals ELUCIDATING THE MOLECULAR MECHANISMS OF MIR-26A ON THE PATHOGENESIS OF ABDOMINAL AORTIC ANEURYSM - IN VITRO STUDIES

2018 ◽  
Vol 34 (10) ◽  
pp. S69-S70
Author(s):  
L. Elfaki ◽  
R. Pirani ◽  
Z. Afrasiabi ◽  
P. Matkar ◽  
H. Chen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
In Vitro Studies ◽  
Abdominal Aortic

scholarly journals Recent Advances in Molecular Mechanisms of Abdominal Aortic Aneurysm Formation

2008 ◽  
Vol 32 (6) ◽  
pp. 976-986 ◽  
Author(s):  
Suman Annambhotla ◽  
Sebastian Bourgeois ◽  
Xinwen Wang ◽  
Peter H. Lin ◽  
Qizhi Yao ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Aneurysm Formation ◽  
Recent Advances ◽  
Abdominal Aortic

scholarly journals CRP immunodeposition and proteomic analysis in abdominal aortic aneurysm

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0245361
Author(s):  
Eun Na Kim ◽  
Jiyoung Yu ◽  
Joon Seo Lim ◽  
Hwangkyo Jeong ◽  
Chong Jai Kim ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Signaling Pathways ◽  
Proteomic Analysis ◽  
Molecular Mechanisms ◽  
Aortic Wall ◽  
High Serum ◽  
Maximal Diameter ◽  
Abdominal Aortic ◽  
Serum Crp

Objective The molecular mechanisms of the degeneration of the aortic wall in abdominal aortic aneurysm (AAA) are poorly understood. The monomeric form of C-reactive protein (mCRP) is deposited in damaged cardiovascular organs and aggravates the prognosis; however, it is unknown whether mCRP is deposited in the degenerated aorta of abdominal aortic aneurysm (AAA). We investigated whether mCRP is deposited in AAA and examined the associated pathogenic signaling pathways. Methods Twenty-four cases of AAA were analyzed and their histological features were compared according to the level of serum CRP and the degree of mCRP deposition. Proteomic analysis was performed in AAA cases with strong and diffuse CRP immunopositivity (n = 7) and those with weak, focal, and junctional CRP immunopositivity (n = 3). Results mCRP was deposited in the aortic specimens of AAA in a characteristic pattern that coincided with the lesion of the diminished elastic layer of the aortic wall. High serum CRP level was associated with stronger mCRP immunopositivity and a larger maximal diameter of aortic aneurysm. Proteomic analysis in AAA showed that multiple proteins were differentially expressed according to mCRP immunopositivity. Also, ingenuity pathway analysis showed that pathways associated with atherosclerosis, acute phase response, complement system, immune system, and coagulation were enriched in AAA cases with high mCRP immunopositivity. Conclusions AAA showed a characteristic deposition of mCRP, and multiple potentially pathologic signaling pathways were upregulated in AAA cases with strong CRP immunopositivity. mCRP and the aforementioned pathological pathways may serve as targets for managing the progression of AAA.

Management of Abdominal Aortic Aneurysm Disease: Similarities and Differences Among Cardiovascular Guidelines and NICE Guidance

2020 ◽  
Vol 27 (6) ◽  
pp. 889-901
Author(s):  
Konstantinos Spanos ◽  
Petroula Nana ◽  
Christian-Alexander Behrendt ◽  
George Kouvelos ◽  
Giuseppe Panuccio ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Standard Of Care ◽  
Aortic Disease ◽  
Diagnostic Methods ◽  
Treatment Modalities ◽  
Cochrane Central Register ◽  
Abdominal Aortic

The development of endovascular techniques has improved abdominal aortic aneurysm (AAA) management over the past 2 decades. Different cardiovascular societies worldwide have recommended the endovascular approach as the standard of care in their currently available guidelines. While endovascular treatment has established its role in daily clinical practice, a new debate has arisen regarding the indications, appropriateness, limitations, and role of open surgery. To inform this debate, the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from 2010 to May 2020; the systematic search identified 5 articles published between 2011 and 2020 by 4 cardiovascular societies and the National Institute of Health and Care Excellence (NICE). Four debatable domains were assessed and analyzed: diagnostic methods and screening, preoperative management, indications and treatment modalities, and postoperative follow-up and endoleak management. The review addresses controversial proposals as well as widely accepted recommendations and “gray zone” issues that need to be further investigated and analyzed, such as screening in women, medical management, and follow-up imaging. While the recommendations for AAA management have significant overlap and agreement among international cardiovascular societies, the NICE guidelines diverge regarding the role of open repair in aortic disease, recommending conventional surgery in most elective cases.

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