Identification of key genes associated with congenital heart defects in embryos of diabetic mice

Lin,Nan; Cai,Yan; Zhang,Linlin; Chen,Yahang

doi:10.3892/mmr.2017.8330

Identification of key genes associated with congenital heart defects in embryos of diabetic mice

Authors:
- Nan Lin
- Yan Cai
- Linlin Zhang
- Yahang Chen
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Affiliations: Department of Obstetrics and Gynecology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Gastroenterology Department, Harbin The First Hospital, Harbin, Heilongjiang 150001, P.R. China, Department of Obstetrics and Gynecology, The Hospital of Heilongjiang, Harbin, Heilongjiang 150001, P.R. China
Published online on: December 20, 2017 https://doi.org/10.3892/mmr.2017.8330
Pages: 3697-3707
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Maternal diabetes has been reported to be a critical factor for congenital heart defects (CHD) in offspring. The present study aimed to screen the key genes that may be involved in CHD in offspring of diabetic mothers. The present study obtained the gene expression profile of GSE32078, including three embryonic heart tissue samples at embryonic day 13.5 (E13.5), three embryonic heart tissue samples at embryonic day 15.5 (E15.5) from diabetic mice and their respective controls from normal mice. The cut‑off criterion of P<0.08 was set to screen differentially expressed genes (DEGs). Their enrichment functions were predicted by Gene Ontology. The enriched pathways were forecasted by Kyoto Encyclopedia of Genes and Genomes and Reactome analysis. Protein‑protein interaction (PPI) networks for DEGs were constructed using Cytoscape. The present study identified 869 and 802 DEGs in E13.5 group and E15.5 group, respectively and 182 DEGs were shared by the two developmental stages. The pathway enrichment analysis results revealed that DEGs including intercellular adhesion molecule 1 (Icam1) and H2‑M9 were enriched in cell adhesion molecules; DEGs including bone morphogenetic protein receptor type 1A, transforming growth factor β receptor 1 and SMAD specific E3 ubiquitin protein ligase 1 were enriched in the tumor growth factor‑β signaling pathway. In addition, DEGs including Icam1, C1s and Fc fragment of IgG receptor IIb were enriched in Staphylococcus aureus infection. Furthermore, the shared DEGs including Icam1, nuclear receptor corepressor 1 (Ncor1) and AKT serine/threonine kinase 3 (Akt3) had high connectivity degrees in the PPI network. The shared DEGs including Icam1, Ncor1 and Akt3 may be important in the cardiogenesis of embryos. These genes may be involved in the development of CHD in the offspring of diabetic mothers.

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1	Association AD: Diagnosis and classification of diabetes mellitus. Diabetes Care. 33 Supplement 1:S62–S69. 2010. View Article : Google Scholar : PubMed/NCBI
2	Rother KI: Diabetes treatment-bridging the divide. N Engl J Med. 356:1499–1501. 2007. View Article : Google Scholar : PubMed/NCBI
3	Kim C, Newton KM and Knopp RH: Gestational diabetes and the incidence of type 2 diabetes: A systematic review. Diabetes Care. 25:1862–1868. 2002. View Article : Google Scholar : PubMed/NCBI
4	Vijaya M, Manikandan J, Parakalan R, Dheen ST, Kumar SD and Tay SS: Differential gene expression profiles during embryonic heart development in diabetic mice pregnancy. Gene. 516:218–227. 2013. View Article : Google Scholar : PubMed/NCBI
5	Herrera E and Ortega-Senovilla H: Disturbances in lipid metabolism in diabetic pregnancy-are these the cause of the problem? Best Pract Res Clin Endocrinol Metab. 24:515–525. 2010. View Article : Google Scholar : PubMed/NCBI
6	Fahed AC, Gelb BD, Seidman JG and Seidman CE: Genetics of congenital heart disease: The glass half empty. Circ Res. 112:707–720. 2013. View Article : Google Scholar : PubMed/NCBI
7	Molin DG, Roest PA, Nordstrand H, Wisse LJ, Poelmann RE, Eriksson UJ and Gittenberger-De Groot AC: Disturbed morphogenesis of cardiac outflow tract and increased rate of aortic arch anomalies in the offspring of diabetic rats. Birth Defects Res A Clin Mol Teratol. 70:927–938. 2004. View Article : Google Scholar : PubMed/NCBI
8	Dinleyici EC, Tekin N, Dinleyici M, Kilic Z, Adapinar B and Aksit MA: Severe fatal course of axial mesodermal dysplasia spectrum associated with complex cardiac defect in an infant of a mother with insulin dependent diabetes. Am J Med Genet A. 15:2156–2159. 2007. View Article : Google Scholar
9	Pavlinkova G, Salbaum JM and Kappen C: Maternal diabetes alters transcriptional programs in the developing embryo. BMC Genomics. 10:2742009. View Article : Google Scholar : PubMed/NCBI
10	Jiang B, Kumar SD, Loh WT, Manikandan J, Ling EA, Tay SS and Dheen ST: Global gene expression analysis of cranial neural tubes in embryos of diabetic mice. J Neurosci Res. 86:3481–3493. 2008. View Article : Google Scholar : PubMed/NCBI
11	Camenisch TD, Molin DG, Person A, Runyan RB, Gittenberger-de Groot AC, McDonald JA and Klewer SE: Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol. 248:170–181. 2002. View Article : Google Scholar : PubMed/NCBI
12	Han M, Yang X, Farrington JE and Muneoka K: Digit regeneration is regulated by Msx1 and BMP4 in fetal mice. Development. 130:5123–5132. 2003. View Article : Google Scholar : PubMed/NCBI
13	Wang J, Sridurongrit S, Dudas M, Thomas P, Nagy A, Schneider MD, Epstein JA and Kaartinen V: Atrioventricular cushion transformation is mediated by ALK2 in the developing mouse heart. Dev Biol. 286:299–310. 2005. View Article : Google Scholar : PubMed/NCBI
14	Conway SJ, Henderson DJ and Copp AJ: Pax3 is required for cardiac neural crest migration in the mouse: Evidence from the splotch (Sp2H) mutant. Development. 124:505–514. 1997.PubMed/NCBI
15	Kumar SD, Dheen ST and Tay SS: Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development. Cardiovasc Diabetol. 6:342007. View Article : Google Scholar : PubMed/NCBI
16	Kumar SD, Yong SK, Dheen ST, Bay BH and Tay SS: Cardiac malformations are associated with altered expression of vascular endothelial growth factor and endothelial nitric oxide synthase genes in embryos of diabetic mice. Exp Biol Med. 233:1421–1432. 2008. View Article : Google Scholar
17	Gautier L, Cope L, Bolstad BM and Irizarry RA: Affy-analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 20:307–315. 2004. View Article : Google Scholar : PubMed/NCBI
18	Wettenhall JM and Smyth GK: LimmaGUI: A graphical user interface for linear modeling of microarray data. Bioinformatics. 20:3705–3706. 2004. View Article : Google Scholar : PubMed/NCBI
19	Yu G, Wang LG, Han Y and He QY: Clusterprofiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
20	Yu G: Using clusterProfiler to identify and compare functional profiles of gene lists. 2014.
21	Haw R, Hermjakob H, D'Eustachio P and Stein L: Reactome pathway analysis to enrich biological discovery in proteomics data sets. Proteomics. 11:3598–3613. 2011. View Article : Google Scholar : PubMed/NCBI
22	Fabregat A, Sidiropoulos K, Garapati P, et al: The reactome pathway knowledgebase. Nucleic Acids Research. 44:D481–D487. 2015. View Article : Google Scholar : PubMed/NCBI
23	Kohl M, Wiese S and Warscheid B: Cytoscape: Software for visualization and analysis of biological networksData Mining in Proteomics. Springer; pp. 291–303. 2011
24	van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ and Roos-Hesselink JW: Birth prevalence of congenital heart disease worldwide: A systematic review and meta-analysis. J Am Coll Cardiol. 58:2241–2247. 2011. View Article : Google Scholar : PubMed/NCBI
25	Gilboa SM, Correa A, Botto LD, Rasmussen SA, Waller DK, Hobbs CA, Cleves MA and Riehle-Colarusso TJ; National Birth Defects Prevention Study, : Association between prepregnancy body mass index and congenital heart defects. Am J Obstet Gynecol. 202:51.e1–51.e10. 2010. View Article : Google Scholar
26	Lisowski LA, Verheijen PM, Copel JA, Kleinman CS, Wassink S, Visser GH and Meijboom EJ: Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis. Herz. 35:19–26. 2010. View Article : Google Scholar : PubMed/NCBI
27	Buraczynska M, Zaluska W, Baranowicz-Gaszczyk I, Buraczynska K, Niemczyk E and Ksiazek A: The intercellular adhesion molecule-1 (ICAM-1) gene polymorphism K469E in end-stage renal disease patients with cardiovascular disease. Hum Immunol. 73:824–828. 2012. View Article : Google Scholar : PubMed/NCBI
28	Iiyama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD and Cybulsky MI: Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res. 85:199–207. 1999. View Article : Google Scholar : PubMed/NCBI
29	Meerschaert J and Furie MB: The adhesion molecules used by monocytes for migration across endothelium include CD11a/CD18, CD11b/CD18 and VLA-4 on monocytes and ICAM-1, VCAM-1, and other ligands on endothelium. J Immunol. 154:4099–4112. 1995.PubMed/NCBI
30	Toyozaki T, Saito T, Takano H, Yorimitsu K, Kobayashi S, Ichikawa H, Takeda K and Inagaki Y: Expression of intercellular adhesion molecule-1 on cardiac myocytes for myocarditis before and during immunosuppressive therapy. Am J Cardiol. 72:441–444. 1993. View Article : Google Scholar : PubMed/NCBI
31	Seko Y, Matsuda H, Kato K, Hashimoto Y, Yagita H, Okumura K and Yazaki Y: Expression of intercellular adhesion molecule-1 in murine hearts with acute myocarditis caused by coxsackievirus B3. J Clin Invest. 91:1327–1336. 1993. View Article : Google Scholar : PubMed/NCBI
32	Seko Y, Yamazaki T, Shinkai Y, Yagita H, Okumura K, Naito S, Imataka K, Fujii J and Yazaki Y: Cellular and molecular bases for the immunopathology of the myocardial cell damage involved in acute viral myocarditis with special reference to dilated cardiomyopathy. Jpn Circ J. 56:1062–1072. 1992. View Article : Google Scholar : PubMed/NCBI
33	Donath MY and Shoelson SE: Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 11:98–107. 2011. View Article : Google Scholar : PubMed/NCBI
34	Duan M, Yao H, Hu G, Chen X, Lund AK and Buch S: HIV Tat induces expression of ICAM-1 in HUVECs: Implications for miR-221/-222 in HIV-associated cardiomyopathy. PLoS One. 8:e601702013. View Article : Google Scholar : PubMed/NCBI
35	Alvarez D, Briassouli P, Clancy RM, Zavadil J, Reed JH, Abellar RG, Halushka M, Fox-Talbot K, Barrat FJ and Buyon JP: A novel role of endothelin-1 in linking Toll-like receptor 7-mediated inflammation to fibrosis in congenital heart block. J Biol Chem. 286:30444–30454. 2011. View Article : Google Scholar : PubMed/NCBI
36	Yamamoto H, Williams EG, Mouchiroud L, Cantó C, Fan W, Downes M, Héligon C, Barish GD, Desvergne B, Evans RM, et al: NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell. 147:827–839. 2011. View Article : Google Scholar : PubMed/NCBI
37	Lockhart MM, Wirrig EE, Phelps AL, Ghatnekar AV, Barth JL, Norris RA and Wessels A: Mef2c regulates transcription of the extracellular matrix protein cartilage link protein 1 in the developing murine heart. PLoS One. 8:e570732013. View Article : Google Scholar : PubMed/NCBI
38	Planavila A, Dominguez E, Navarro M, Vinciguerra M, Iglesias R, Giralt M, Lope-Piedrafita S, Ruberte J and Villarroya F: Dilated cardiomyopathy and mitochondrial dysfunction in Sirt1-deficient mice: A role for Sirt1-Mef2 in adult heart. J Mol Cell Cardiol. 53:521–531. 2012. View Article : Google Scholar : PubMed/NCBI
39	Ventura-Clapier R, Garnier A and Veksler V: Energy metabolism in heart failure. J Physiol. 555:1–13. 2004. View Article : Google Scholar : PubMed/NCBI
40	Pirinccioglu AG, Alyan O, Kizil G, Kangin M and Beyazit N: Evaluation of oxidative stress in children with congenital heart defects. Pediatr Int. 54:94–98. 2012. View Article : Google Scholar : PubMed/NCBI
41	Vinciguerra M, Santini MP, Martinez C, Pazienza V, Claycomb WC, Giuliani A and Rosenthal N: mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart. Aging Cell. 11:139–149. 2012. View Article : Google Scholar : PubMed/NCBI
42	Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF and Sadoshima J: Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res. 100:1512–1521. 2007. View Article : Google Scholar : PubMed/NCBI
43	Mottis A, Mouchiroud L and Auwerx J: Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev. 27:819–835. 2013. View Article : Google Scholar : PubMed/NCBI
44	Hers I, Vincent EE and Tavaré JM: Akt signalling in health and disease. Cell Signal. 23:1515–1527. 2011. View Article : Google Scholar : PubMed/NCBI
45	Chang Z, Zhang Q, Feng Q, Xu J, Teng T, Luan Q, Shan C, Hu Y, Hemmings BA, Gao X and Yang Z: Deletion of Akt1 causes heart defects and abnormal cardiomyocyte proliferation. Dev Biol. 347:384–391. 2010. View Article : Google Scholar : PubMed/NCBI
46	Dimopoulos K, Diller GP, Koltsida E, Pijuan-Domenech A, Papadopoulou SA, Babu-Narayan SV, Salukhe TV, Piepoli MF, Poole-Wilson PA, Best N, et al: Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease. Circulation. 117:2320–2328. 2008. View Article : Google Scholar : PubMed/NCBI