Dissecting the mechanism of carotid atherosclerosis from the perspective of regulation

Lin,Min; Zhao,Lin; Zhao,Wenlong; Weng,Jing

doi:10.3892/ijmm.2014.1960

Dissecting the mechanism of carotid atherosclerosis from the perspective of regulation

Authors:
- Min Lin
- Lin Zhao
- Wenlong Zhao
- Jing Weng
View Affiliations

Affiliations: Department of Neurology, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, P.R. China, Department of Neurosurgery, Fuzhou General Hospital of Nanjing Command, PLA, Fuzhou 350025, P.R. China
Published online on: October 9, 2014 https://doi.org/10.3892/ijmm.2014.1960
Pages: 1458-1466
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Carotid atherosclerosis is a chronic inflammatory disease of the arterial wall. The present study aimed to identify changes in the gene expression and regulatory factors for atherosclerotic plaques of carotid atherosclerosis from an early to an advanced stage. The original data were downloaded from the NCBI GEO database under accession no. GSE28829. Differentially expressed genes (DEGs) were detected by the Robust Multiarray Average (RMA). The enriched Gene Ontology (GO) terms and pathways for DEGs using DAVID were subsequently identified. The transcriptional and microRNA (miRNA) regulatory network were constructed for the DEGs. Cis-regulatory signals were also investigated. More genes were activated in the advanced stage compared with the early stage. IGHG1 and SPP1 were upregulated, while MYBL1 and PLD were downregulated. The upregulated genes in the advanced stage were involved in atherosclerosis‑related GO terms such as immune, vascular and cell movement homeostasis. The DEGs were significantly enriched in cell adhesion molecules (CAMs) and the focal adhesion pathway. MMP9 and CFL2 played key roles in the transcriptional regulatory network. Moreover, miR-328 was identified as one of the hubs in the miRNA regulatory network. The results may therefore be used to determine the mechanism involved in carotid atherosclerosis.

View Figures

View References

1	Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 362:801–809. 1993. View Article : Google Scholar : PubMed/NCBI
2	Maseri A and Fuster V: Is there a vulnerable plaque? Circulation. 107:2068–2071. 2003. View Article : Google Scholar : PubMed/NCBI
3	Ross R: Atherosclerosis - an inflammatory disease. N Engl J Med. 340:115–126. 1999. View Article : Google Scholar
4	O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL and Wolfson SK Jr: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 340:14–22. 1999.
5	Wu Y, Tao Z, Song C, et al: Overexpression of YKL-40 predicts plaque instability in carotid atherosclerosis with CagA-positive helicobacter pylori infection. PLoS One. 8:e599962013. View Article : Google Scholar : PubMed/NCBI
6	Yamada M, Kim S, Egashira K, et al: Molecular mechanism and role of endothelial monocyte chemoattractant protein-1 induction by vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 23:1996–2001. 2003. View Article : Google Scholar : PubMed/NCBI
7	Leng XY, Chen XY, Chook P, et al: Association between metabolic syndrome and carotid atherosclerosis: a community-based study in Hong Kong. Metab Syndr Relat Disord. 11:109–114. 2013. View Article : Google Scholar : PubMed/NCBI
8	Ota H, Reeves MJ, Zhu DC, et al: Sex differences of high-risk carotid atherosclerotic plaque with less than 50% stenosis in asymptomatic patients: an in vivo 3T MRI study. AJNR Am J Neuroradiol. 34:1049–1055. 2013.PubMed/NCBI
9	Ino-Oka E, Sekino H, Kajikawa S, Satoh T and Inooka H: Evaluation of carotid atherosclerosis from the perspective of blood flow reflection. Clin Exp Hypertens. 31:188–200. 2009. View Article : Google Scholar : PubMed/NCBI
10	Maeda S, Sawayama Y, Furusyo N, Shigematsu M and Hayashi J: The association between fatal vascular events and risk factors for carotid atherosclerosis in patients on maintenance hemodialysis: plaque number of dialytic atherosclerosis study. Atherosclerosis. 204:549–555. 2009. View Article : Google Scholar
11	Munakata M, Sakuraba J, Tayama J, et al: Higher brachial-ankle pulse wave velocity is associated with more advanced carotid atherosclerosis in end-stage renal disease. Hypertens Res. 28:9–14. 2005. View Article : Google Scholar : PubMed/NCBI
12	Hashimoto H, Kitagawa K, Kuwabara K, et al: Circulating adhesion molecules are correlated with ultrasonic assessment of carotid plaques. Clin Sci (Lond). 104:521–527. 2003. View Article : Google Scholar : PubMed/NCBI
13	Blin J, Ahmad Z, Rampal LR, Mohtarrudin N, Tajudin AK and Adnan RS: Preliminary assessment of differential expression of candidate genes associated with atherosclerosis. Genes Genet Syst. 88:199–209. 2013.PubMed/NCBI
14	Inouye M, Ripatti S, Kettunen J, et al: Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. PLoS Genet. 8:e10029072012. View Article : Google Scholar : PubMed/NCBI
15	Bateman HR, Liang Q, Fan D, Rodriguez V and Lessner SM: Sparstolonin B inhibits pro-angiogenic functions and blocks cell cycle progression in endothelial cells. PLoS One. 8:e705002013. View Article : Google Scholar : PubMed/NCBI
16	Feig JE, Vengrenyuk Y, Reiser V, et al: Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLoS One. 7:e397902012. View Article : Google Scholar : PubMed/NCBI
17	Zhang E and Wu Y: Dual effects of miR-155 on macrophages at different stages of atherosclerosis: LDL is the key? Med Hypotheses. 2014. 83:74–78. 2014. View Article : Google Scholar : PubMed/NCBI
18	Bonaterra GA, Zugel S, Thogersen J, et al: Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent inflammatory response to vascular injury. J Am Heart Assoc. 1:e0025502012. View Article : Google Scholar
19	Orr AW, Hastings NE, Blackman BR and Wamhoff BR: Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis. J Vasc Res. 47:168–180. 2010. View Article : Google Scholar : PubMed/NCBI
20	States JC, Singh AV, Knudsen TB, et al: Prenatal arsenic exposure alters gene expression in the adult liver to a proinflammatory state contributing to accelerated atherosclerosis. PLoS One. 7:e387132012. View Article : Google Scholar : PubMed/NCBI
21	Bahls M, Bidwell CA, Hu J, et al: Gene expression differences during the heterogeneous progression of peripheral atherosclerosis in familial hypercholesterolemic swine. BMC Genomics. 14:4432013. View Article : Google Scholar : PubMed/NCBI
22	Pinkaew D, Hutadilok-Towatana N, Teng BB, Mahabusarakam W and Fujise K: Morelloflavone, a biflavonoid inhibitor of migration-related kinases, ameliorates atherosclerosis in mice. Am J Physiol Heart Circ Physiol. 302:H451–H458. 2012. View Article : Google Scholar : PubMed/NCBI
23	Doring Y, Manthey HD, Drechsler M, et al: Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation. 125:1673–1683. 2012. View Article : Google Scholar : PubMed/NCBI
24	Irizarry RA, Hobbs B, Collin F, et al: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 4:249–264. 2003. View Article : Google Scholar
25	Philip R: Semantic similarity in a taxonomy: an information-based measure and its application to problems of ambiguity in natural language. J Artif Intell Res. 11:95–130. 1999.
26	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.PubMed/NCBI
27	Portales-Casamar E, Thongjuea S, Kwon AT, et al: JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles. Nucleic Acids Res. 38:D105–D110. 2010. View Article : Google Scholar : PubMed/NCBI
28	Wang K, Hu F, Xu K, et al: CASCADE_SCAN: mining signal transduction network from high-throughput data based on steepest descent method. BMC Bioinformatics. 12:1642011. View Article : Google Scholar : PubMed/NCBI
29	Kruger J and Rehmsmeier M: RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res. 34:W451–W454. 2006. View Article : Google Scholar : PubMed/NCBI
30	Li LX, Zhao CC, Ren Y, et al: Prevalence and clinical characteristics of carotid atherosclerosis in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study. Cardiovasc Diabetol. 12:182013. View Article : Google Scholar
31	Li X, Ni R, Chen J, et al: The presence of IGHG1 in human pancreatic carcinomas is associated with immune evasion mechanisms. Pancreas. 40:753–761. 2011. View Article : Google Scholar : PubMed/NCBI
32	Pan B, Zheng S, Liu C and Xu Y: Suppression of IGHG1 gene expression by siRNA leads to growth inhibition and apoptosis induction in human prostate cancer cell. Mol Biol Rep. 40:27–33. 2013. View Article : Google Scholar : PubMed/NCBI
33	Kitaya K, Yasuo T, Yamaguchi T, Fushiki S and Honjo H: Genes regulated by interferon-γ in human uterine microvascular endothelial cells. Int J Mol Med. 20:689–697. 2007.
34	Shan M, Yuan X, Song LZ, et al: Cigarette smoke induction of osteopontin (SPP1) mediates T_H17 inflammation in human and experimental emphysema. Sci Transl Med. 4:117ra92012. View Article : Google Scholar : PubMed/NCBI
35	Lohr M, Edlund K, Botling J, et al: The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer. Cancer Lett. 333:222–228. 2013. View Article : Google Scholar : PubMed/NCBI
36	Whiteside TL and Ferrone S: IGKC and prognosis in breast cancer - response to Schmidt. Clin Cancer Res. 19:3052013. View Article : Google Scholar : PubMed/NCBI
37	Schmidt M, Micke P and Hengstler JG: IGKC and prognosis in breast cancer. Clin Cancer Res. 19:3042013. View Article : Google Scholar : PubMed/NCBI
38	Luchtefeld M, Preuss C, Ruhle F, et al: Gp130-dependent release of acute phase proteins is linked to the activation of innate immune signaling pathways. PLoS One. 6:e194272011. View Article : Google Scholar : PubMed/NCBI
39	Hahn C and Schwartz MA: Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol. 10:53–62. 2009. View Article : Google Scholar : PubMed/NCBI
40	Sjoland H, Eitzman DT, Gordon D, Westrick R, Nabel EG and Ginsburg D: Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol. 20:846–852. 2000. View Article : Google Scholar : PubMed/NCBI
41	Languino LR, Duperray A, Joganic KJ, Fornaro M, Thornton GB and Altieri DC: Regulation of leukocyte-endothelium interaction and leukocyte transendothelial migration by intercellular adhesion molecule 1-fibrinogen recognition. Proc Natl Acad Sci USA. 92:1505–1509. 1995. View Article : Google Scholar
42	Alonso DR, Starek PK and Minick CR: Studies on the pathogenesis of atheroarteriosclerosis induced in rabbit cardiac allografts by the synergy of graft rejection and hypercholesterolemia. Am J Pathol. 87:415–442. 1977.PubMed/NCBI
43	McLeod DS: Autoimmune thyroid disease: a novel risk factor for atherosclerosis? Endocrine. 44:8–10. 2013. View Article : Google Scholar : PubMed/NCBI
44	Bu DX, Rai V, Shen X, et al: Activation of the ROCK1 branch of the transforming growth factor-β pathway contributes to RAGE-dependent acceleration of atherosclerosis in diabetic ApoE-null mice. Circ Res. 106:1040–1051. 2010.PubMed/NCBI
45	Richez C, Richards RJ, Duffau P, et al: The effect of mycophenolate mofetil on disease development in the gld.apoE^−/− mouse model of accelerated atherosclerosis and systemic lupus erythematosus. PLoS One. 8:e610422013.PubMed/NCBI
46	Hashemi M, Saadat M, Behjati M and Kelishadi R: Comparison of serum apolipoprotein levels of diabetic children and healthy children with or without diabetic parents. Cholesterol. 2012:4903812012. View Article : Google Scholar : PubMed/NCBI
47	Samson T, van Buul JD, Kroon J, et al: The guanine-nucleotide exchange factor SGEF plays a crucial role in the formation of atherosclerosis. PLoS One. 8:e552022013. View Article : Google Scholar : PubMed/NCBI
48	Schmitz G and Buechler C: ABCA1: regulation, trafficking and association with heteromeric proteins. Ann Med. 34:334–347. 2002. View Article : Google Scholar : PubMed/NCBI
49	Wang X, Venable J, LaPointe P, et al: Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell. 127:803–815. 2006. View Article : Google Scholar : PubMed/NCBI
50	Lemaire M, Lemarie CA, Molina MF, Schiffrin EL, Lehoux S and Mann KK: Exposure to moderate arsenic concentrations increases atherosclerosis in ApoE^−/− mouse model. Toxicol Sci. 122:211–221. 2011. View Article : Google Scholar : PubMed/NCBI
51	Srivastava S, Vladykovskaya EN, Haberzettl P, Sithu SD, D’Souza SE and States JC: Arsenic exacerbates atherosclerotic lesion formation and inflammation in ApoE−/− mice. Toxicol Appl Pharmacol. 241:90–100. 2009.PubMed/NCBI
52	Suarez Y and Sessa WC: MicroRNAs as novel regulators of angiogenesis. Circ Res. 104:442–454. 2009. View Article : Google Scholar : PubMed/NCBI
53	Caruthers SD, Cyrus T, Winter PM, Wickline SA and Lanza GM: Anti-angiogenic perfluorocarbon nanoparticles for diagnosis and treatment of atherosclerosis. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 1:311–323. 2009. View Article : Google Scholar : PubMed/NCBI
54	Li X, Pan YZ, Seigel GM, Hu ZH, Huang M and Yu AM: Breast cancer resistance protein BCRP/ABCG2 regulatory microRNAs (hsa-miR-328, -519c and -520h) and their differential expression in stem-like ABCG2⁺ cancer cells. Biochem Pharmacol. 81:783–792. 2011. View Article : Google Scholar
55	Wang X, Qiu CG, Huang ZW, Han ZY, Lu WJ and Chen XJ: The expression and clinical implication of plasma miR-328 in patients with atrial fibrillation. Zhonghua Xin Xue Guan Bing Za Zhi. 41:126–129. 2013.(In Chinese).