Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile

Chen,Xudong; Zheng,Chengfei; He,Yunjun; Tian,Lu; Li,Jianhui; Li,Donglin; Jin,Wei; Li,Ming; Zheng,Shusen

doi:10.3892/mmr.2015.4448

Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile

Authors:
- Xudong Chen
- Chengfei Zheng
- Yunjun He
- Lu Tian
- Jianhui Li
- Donglin Li
- Wei Jin
- Ming Li
- Shusen Zheng
View Affiliations

Affiliations: Department of Vascular Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: October 15, 2015 https://doi.org/10.3892/mmr.2015.4448
Pages: 7891-7898
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study was aimed at screening the key genes associated with abdominal aortic aneurysm (AAA) in the neck, and to investigate the molecular mechanism underlying the development of AAA. The gene expression profile, GSE47472, including 14 AAA neck samples and eight donor controls, was downloaded from the Gene Expression Omnibus database. The total AAA samples were grouped into two types to avoid bias. Differentially expressed genes (DEGs) were screened in patients with AAA and subsequently compared with donor controls using linear models for microarray data, or the Limma package in R, followed by gene ontology enrichment analysis. Furthermore, a protein‑protein interaction (PPI) network based on the DEGs was constructed to detect highly connected regions using a Cytoscape plugin. In total, 388 DEGs in the AAA samples were identified. These DEGs were predominantly associated with limb development, including embryonic limb development and appendage development. Nuclear receptor co‑repressor 1 (NCOR1), histone 4 (H4), E2F transcription factor 4 (E2F4) and hepatocyte nuclear factor 4α (HNF4A) were the four transcription factors associated with AAA. Furthermore, HNF4A indirectly interacted with the other three transcription factors. Additionally, six clusters were selected from the PPI network. The DEG screening process and the construction of an interaction network enabled an understanding of the mechanism of AAA to be gleaned. HNF4A may exert an important role in AAA development through its interactions with the three other transcription factors (E2F4, NCOR1 and H4), and the mechanism of this coordinated regulation of the transcription factors in AAA may provide a suitable target for the development of therapeutic intervention strategies.

View Figures

View References

1	Golledge J, Muller J, Daugherty A and Norman P: Abdominal aortic aneurysm: Pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 26:2605–2613. 2006. View Article : Google Scholar : PubMed/NCBI
2	Maegdefessel L, Dalman RL and Tsao PS: Pathogenesis of abdominal aortic aneurysms: MicroRNAs, proteases, genetic associations. Annu Rev Med. 65:49–62. 2014. View Article : Google Scholar
3	Verhoeven EL, Kapma MR, Groen H, Tielliu IF, Zeebregts CJ, Bekkema F and van den Dungen JJ: Mortality of ruptured abdominal aortic aneurysm treated with open or endovascular repair. J Vasc Surg. 48:1396–1400. 2008. View Article : Google Scholar : PubMed/NCBI
4	Golledge J and Norman PE: Current status of medical management for abdominal aortic aneurysm. Atherosclerosis. 217:57–63. 2011. View Article : Google Scholar : PubMed/NCBI
5	Sakalihasan N, Limet R and Defawe O: Abdominal aortic aneurysm. The Lancet. 365:1577–1589. 2005. View Article : Google Scholar
6	Michel JB, Martin-Ventura JL, Egido J, Sakalihasan N, Treska V, Lindholt J, Allaire E, Thorsteinsdottir U, Cockerill G and Swedenborg J; FAD EU Consortium: Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc Res. 90:18–27. 2011. View Article : Google Scholar :
7	Thomas M, Gavrila D, McCormick ML, Miller FJ Jr, Daugherty A, Cassis LA, Dellsperger KC and Weintraub NL: Deletion of p47phox attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-deficient mice. Circulation. 114:404–413. 2006. View Article : Google Scholar : PubMed/NCBI
8	Sharma AK, Lu G, Jester A, Johnston WF, Zhao Y, Hajzus VA, Saadatzadeh MR, Su G, Bhamidipati CM, Mehta GS, et al: Experimental abdominal aortic aneurysm formation is mediated by IL-17 and attenuated by mesenchymal stem cell treatment. Circulation. 126(Suppl 1): S38–S45. 2012. View Article : Google Scholar : PubMed/NCBI
9	Harrison SC, Smith AJ, Jones GT, Swerdlow DI, Rampuri R, Bown MJ; Aneurysm Consortium; Folkersen L, Baas AF, de Borst GJ, et al: Interleukin-6 receptor pathways in abdominal aortic aneurysm. Eur Heart J. 34:3707–3716. 2013. View Article : Google Scholar :
10	Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, et al: Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p-21 dependent pathway. Circulation. 114:953–960. 2006. View Article : Google Scholar : PubMed/NCBI
11	Manning MW, Cassis LA and Daugherty A: Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 23:483–488. 2003. View Article : Google Scholar
12	Hinterseher I, Tromp G and Kuivaniemi H: Genes and abdominal aortic aneurysm. Ann Vasc Surg. 25:388–412. 2011. View Article : Google Scholar :
13	Hinterseher I, Erdman R, Elmore JR, Stahl E, Pahl MC, Derr K, Golden A, Lillvis JH, Cindric MC, Jackson K, et al: Novel pathways in the pathobiology of human abdominal aortic aneurysms. Pathobiology. 80:1–10. 2013. View Article : Google Scholar :
14	Golledge J and Kuivaniemi H: Genetics of abdominal aortic aneurysm. Curr Opin Cardiol. 28:290–296. 2013. View Article : Google Scholar : PubMed/NCBI
15	Duftner C, Seiler R, Dejaco C, Fraedrich G and Schirmer M: Increasing evidence for immune-mediated processes and new therapeutic approaches in abdominal aortic aneurysms-a review. Ann N Y Acad Sci. 1085:331–338. 2006. View Article : Google Scholar : PubMed/NCBI
16	Kuivaniemi H, Platsoucas CD and Tilson MD III: Aortic aneurysms: An immune disease with a strong genetic component. Circulation. 117:242–252. 2008. View Article : Google Scholar : PubMed/NCBI
17	Biros E, Moran CS, Rush CM, Gäbel G, Schreurs C, Lindeman JH, Walker PJ, Nataatmadja M, West M, Holdt LM, et al: Differential gene expression in the proximal neck of human abdominal aortic aneurysm. Atherosclerosis. 233:211–218. 2014. View Article : Google Scholar : PubMed/NCBI
18	Dunning MJ, Smith ML, Ritchie ME and Tavaré S: Beadarray: R classes and methods for Illumina bead-based data. Bioinformatics. 23:2183–2184. 2007. View Article : Google Scholar : PubMed/NCBI
19	Bolstad BM: Probe level quantile normalization of high density oligonucleotide array data. Unpublished manuscript. 2001
20	Choi J: Guide: A desktop application for analysing gene expression data. BMC Genomics. 14:6882013. View Article : Google Scholar : PubMed/NCBI
21	Smyth GK: Limma: Linear models for microarray data. Bioinformatics and computational biology solutions using R and Bioconductor. Springer; New York: pp. 397–420. 2005, View Article : Google Scholar
22	Benjamini Y and Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 57:289–300. 1995.
23	Makova KD and Li WH: Divergence in the spatial pattern of gene expression between human duplicate genes. Genome Res. 7:1638–1645. 2003. View Article : Google Scholar
24	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009. View Article : Google Scholar : PubMed/NCBI
25	Huang da W, Sherman BT and Lempicki RA: Bioinformatics enrichment tools: Paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37:1–13. 2009. View Article : Google Scholar :
26	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: Tool for the unification of biology. The gene ontology consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
27	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
28	Martin A, Ochagavia ME, Rabasa LC, Miranda J, Fernandez-de-Cossio J and Bringas R: BisoGenet: A new tool for gene network building, visualization and analysis. BMC Bioinformatics. 11:912010. View Article : Google Scholar : PubMed/NCBI
29	Bader GD, Betel D and Hogue CW: BIND: The biomolecular interaction network database. Nucleic Acids Res. 31:248–250. 2003. View Article : Google Scholar : PubMed/NCBI
30	Nepusz T, Yu H and Paccanaro A: Detecting overlapping protein complexes in protein protein interaction networks. Nat Methods. 9:471–472. 2012. View Article : Google Scholar : PubMed/NCBI
31	Estrelinha M, Hinterseher I and Kuivaniemi H: Gene expression studies in human abdominal aortic aneurysm. Rev Vasc Med. 2:77–82. 2014. View Article : Google Scholar
32	Yoon HG, Chan DW, Reynolds AB, Qin J and Wong J: N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol Cell. 12:723–734. 2003. View Article : Google Scholar : PubMed/NCBI
33	Saratzis A, Abbas AA, Kiskinis D, Melas N, Saratzis N and Kitas GD: Abdominal aortic aneurysm: A review of the genetic basis. Angiology. 62:18–32. 2011. View Article : Google Scholar
34	Mannello F and Medda V: Nuclear localization of matrix metalloproteinases. Prog Histochem Cytochem. 47:27–58. 2012. View Article : Google Scholar : PubMed/NCBI
35	Turner BM, Birley AJ and Lavender J: Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell. 69:375–384. 1992. View Article : Google Scholar : PubMed/NCBI
36	Santos-Rosa H and Caldas C: Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer. 41:2381–2402. 2005. View Article : Google Scholar : PubMed/NCBI
37	Kanazawa T, Konno A, Hashimoto Y and Kon Y: Hepatocyte nuclear factor 4 alpha is associated with survival of the condensed mesenchyme in the developing mouse kidney. Dev Dyn. 239:1145–1154. 2010. View Article : Google Scholar : PubMed/NCBI
38	Sandovici I, Smith NH, Nitert MD, Ackers Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, et al: Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci USA. 108:5449–5454. 2011. View Article : Google Scholar : PubMed/NCBI
39	Zack M, Boyanovsky BB, Shridas P, Bailey W, Forrest K, Howatt DA, Gelb MH, de Beer FC, Daugherty A and Webb NR: Group X secretory phospholipase A(2) augments angiotensin II induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice. Atherosclerosis. 214:58–64. 2011. View Article : Google Scholar
40	Guan M, Qu L, Tan W, Chen L and Wong CW: Hepatocyte nuclear factor-4 alpha regulates liver triglyceride metabolism in part through secreted phospholipase A2 GXIIB. Hepatology. 53:458–466. 2011. View Article : Google Scholar : PubMed/NCBI
41	Soutoglou E, Katrakili N and Talianidis I: Acetylation regulates transcription factor activity at multiple levels. Mol Cell. 5:745–751. 2000. View Article : Google Scholar : PubMed/NCBI
42	Beijersbergen RL, Kerkhoven RM, Zhu L, Carlée L, Voorhoeve PM and Bernards R: E2F-4, a new member of the E2F gene family, has oncogenic activity and associates with p107 in vivo. Genes Dev. 8:2680–2690. 1994. View Article : Google Scholar : PubMed/NCBI
43	Zheng N, Fraenkel E, Pabo CO and Pavletich NP: Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Genes Dev. 13:666–674. 1999. View Article : Google Scholar : PubMed/NCBI
44	Tung WS, Lee JK and Thompson RW: Simultaneous analysis of 1176 gene products in normal human aorta and abdominal aortic aneurysms using a membrane-based complementary DNA expression array. J Vasc Surg. 34:143–150. 2001. View Article : Google Scholar : PubMed/NCBI
45	Talianidis I, Tambakaki A, Toursounova J and Zannis VI: Complex interactions between SP1 bound to multiple distal regulatory sites and HNF-4 bound to the proximal promoter lead to transcriptional activation of liver-specific human APOCIII gene. Biochemistry. 34:10298–10309. 1995. View Article : Google Scholar : PubMed/NCBI
46	Cook T, Gebelein B and Urrutia R: Sp1 and its likes: Biochemical and functional predictions for a growing family of zinc finger transcription factors. Ann N Y Acad Sci. 880:94–102. 1999. View Article : Google Scholar : PubMed/NCBI
47	Price SJ, Greaves DR and Watkins H: Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: Role of Sp1 in allele-specific transcriptional regulation. J Biol Chem. 276:7549–7558. 2001. View Article : Google Scholar
48	Pauklin S and Vallier L: The cell cycle state of stem cells determines cell fate propensity. Cell. 155:135–147. 2013. View Article : Google Scholar : PubMed/NCBI
49	Cooper MD and Alder MN: The evolution of adaptive immune systems. Cell. 124:815–822. 2006. View Article : Google Scholar : PubMed/NCBI
50	Henderson EL, Geng YJ, Sukhova GK, Whittemore AD, Knox J and Libby P: Death of smooth muscle cells and expression of mediators of apoptosis by T lymphocytes in human abdominal aortic aneurysms. Circulation. 99:96–104. 1999. View Article : Google Scholar : PubMed/NCBI