Background: Ischemic cardiomyopathy (ISCM) following myocardial infarction is closely related with a poor prognosis in patients with coronary heart disease. Several researches have showed that noncoding RNAs, including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in the progression of ISCM. The aim of the present study was to explore the potential biomarkers and competing endogenous RNA (ceRNA) machenism in ISCM. Methods: Based on the open-source database, we identified differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) between samples from ISCM patients and controls using affy and limma package in R (absolute log2 fold change ≥1 and p<0.05). We prediced target miRNAs of DELs and DEGs by TargetScanHuman, miRDB and miRTarBase with at least two validations in three databases. Gene ontology (GO) analysis of DEGs was performed by clusterProfiler package in R. Taken the nodes together, we tried to build a net according to ceRNA theory. Results: We integrated the crosstalk of DEGs, DELs and miRNAs and constructed a ceRNA network. There are 21 lncRNAs, 39 miRNAs, and 41 mRNAs involved in the network. Functional analysis showed that DEGs were most prominently associated with molecular functions in extracellular matrix. Conclusion: By constructing ceRNA net in ISCM, we found that several important lncRNAs and genes were included. More nodes need to be verified both in vivo and in vitro.

Yajie Fan, Zhihui Yao, Tuo Han, Lixia Wang, Yiwen Wang, Congxia Wang. The Role of Competing Endogenous RNA (ceRNA) Network in Ischemic Cardiomyopathy by Bioinformatic Analysis. Frontiers in Medical Science Research (2021) Vol. 3 Issue 2: 29-36. https://doi.org/10.25236/FMSR.2021.030208.

[1] Tiyyagura S.R., Pinney S.P. Left ventricular remodeling after myocardial infarction: past, present, and future [J]. Mt Sinai J Med, 2006, 73(6): 840-51.

[2] Braunwald E. Heart Failure [J]. JACC: Heart Failure, 2013, 1(1): 1-20.

[3] Siebert V., Allencherril J., Ye Y., et al. The Role of Non-coding RNAs in Ischemic Myocardial Reperfusion Injury [J]. Cardiovasc Drugs Ther, 2019, 33(4): 489-98.

[4] Xiong W., Qu Y., Chen H., et al. Insight into long noncoding RNA–miRNA–mRNA axes in myocardial ischemia-reperfusion injury: the implications for mechanism and therapy [J]. Epigenomics, 2019, 11(15): 1733-48.

[5] Chen F., Li Z., Deng C., et al. Integrated analysis identifying new lncRNA markers revealed in ceRNA network for tumor recurrence in papillary thyroid carcinoma and build of nomogram [J]. Journal of Cellular Biochemistry, 2019, 120(12): 19673-83.

[6] Tao L., Yang L., Huang X., et al. Reconstruction and Analysis of the lncRNA-miRNA-mRNA Network Based on Competitive Endogenous RNA Reveal Functional lncRNAs in Dilated Cardiomyopathy [J]. Front Genet, 2019, 10(1149.

[7] Barrett T., Wilhite S.E., Ledoux P., et al. NCBI GEO: archive for functional genomics data sets--update [J]. Nucleic Acids Res, 2013, 41(Database issue): D991-5.

[8] Kim E.H., Galchev V.I., Kim J.Y., et al. Differential protein expression and basal lamina remodeling in human heart failure [J]. Proteomics Clin Appl, 2016, 10(5): 585-96.

[9] Greco S., Zaccagnini G., Perfetti A., et al. Long noncoding RNA dysregulation in ischemic heart failure [J]. Journal of Translational Medicine, 2016, 14(1): 

[10] Gautier L., Cope L., Bolstad B.M., et al. affy--analysis of Affymetrix GeneChip data at the probe level [J]. Bioinformatics, 2004, 20(3): 307-15.

[11] Ritchie M.E., Phipson B., Wu D., et al. limma powers differential expression analyses for RNA-sequencing and microarray studies [J]. Nucleic Acids Res, 2015, 43(7): e47.

[12] Yu G., Wang L.G., Han Y., et al. clusterProfiler: an R package for comparing biological themes among gene clusters [J]. OMICS, 2012, 16(5): 284-7.

[13] Jeggari A., Marks D.S., Larsson E. miRcode: a map of putative microRNA target sites in the long non-coding transcriptome [J]. Bioinformatics, 2012, 28(15): 2062-3.

[14] Frankish A., Diekhans M., Ferreira A.M., et al. GENCODE reference annotation for the human and mouse genomes [J]. Nucleic Acids Res, 2019, 47(D1): D766-D73.

[15] Agarwal V., Bell G.W., Nam J.W., et al. Predicting effective microRNA target sites in mammalian mRNAs [J]. Elife, 2015, 4(

[16] Liu W., Wang X. Prediction of functional microRNA targets by integrative modeling of microRNA binding and target expression data [J]. Genome Biol, 2019, 20(1): 18.

[17] Chou C.H., Shrestha S., Yang C.D., et al. miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions [J]. Nucleic Acids Res, 2018, 46(D1): D296-D302.

[18] Shannon P., Markiel A., Ozier O., et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks [J]. Genome Res, 2003, 13(11): 2498-504.

[19] Li X.L., Yu F., Li B.Y., et al. The protective effects of grape seed procyanidin B2 against asporin mediates glycated low-density lipoprotein induced-cardiomyocyte apoptosis and fibrosis [J]. Cell Biol Int, 2019, 

[20] Deckx S., Heymans S., Papageorgiou A.-P. The diverse functions of osteoglycin: a deceitful dwarf, or a master regulator of disease? [J]. The FASEB journal, 2016, 30(8): 2651-61.

[21] Petretto E., Sarwar R., Grieve I., et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass [J]. Nature Genetics, 2008, 40(5): 546-52.

[22] Seki T., Saita E., Kishimoto Y., et al. Low Levels of Plasma Osteoglycin in Patients with Complex Coronary Lesions [J]. Journal of Atherosclerosis and Thrombosis, 2018, 25(11): 1149-55.

[23] Zuo C., Li X., Huang J., et al. Osteoglycin attenuates cardiac fibrosis by suppressing cardiac myofibroblast proliferation and migration through antagonizing lysophosphatidic acid 3/matrix metalloproteinase 2/epidermal growth factor receptor signalling [J]. Cardiovasc Res, 2018, 114(5): 703-12.

[24] Baek S.H., Cha R.H., Kang S.W., et al. Higher Serum Levels of Osteoglycin Are Associated with All-Cause Mortality and Cardiovascular and Cerebrovascular Events in Patients with Advanced Chronic Kidney Disease [J]. Tohoku J Exp Med, 2017, 242(4): 281-90.

[25] Zhao L., Guo Z., Wang P., et al. Proteomics of epicardial adipose tissue in patients with heart failure [J]. Journal of Cellular and Molecular Medicine, 2020, 24(1): 511-20.

[26] Lok S.I., Lok D.J., van der Weide P., et al. Plasma levels of alpha-1-antichymotrypsin are elevated in patients with chronic heart failure, but are of limited prognostic value [J]. Netherlands Heart Journal, 2014, 22(9): 391-5.

[27] Matlung H.L., Neele A.E., Groen H.C., et al. Transglutaminase activity regulates atherosclerotic plaque composition at locations exposed to oscillatory shear stress [J]. Atherosclerosis, 2012, 224(2): 355-62.

[28] Rébé C.d., Raveneau M., Chevriaux A.l., et al. Induction of Transglutaminase 2 by a Liver X Receptor/Retinoic Acid Receptor α Pathway Increases the Clearance of Apoptotic Cells by Human Macrophages [J]. Circulation Research, 2009, 105(4): 393-401.

[29] Sala-Newby G.B., George S.J., Bond M., et al. Regulation of vascular smooth muscle cell proliferation, migration and death by heparan sulfate 6-O-endosulfatase1 [J]. FEBS Lett, 2005, 579(28): 6493-8.

[30] Cha H.J., Kim H.Y., Kim H.S. Sulfatase 1 mediates the attenuation of Ang II-induced hypertensive effects by CCL5 in vascular smooth muscle cells from spontaneously hypertensive rats [J]. Cytokine, 2018, 110(1-8.

[31] Korf-Klingebiel M., Reboll M.R., Grote K., et al. Heparan Sulfate–Editing Extracellular Sulfatases Enhance VEGF Bioavailability for Ischemic Heart Repair [J]. Circulation Research, 2019, 125(9): 787-801.

[32] Luo H., Wang J., Liu D., et al. The lncRNA H19/miR-675 axis regulates myocardial ischemic and reperfusion injury by targeting PPARα [J]. Molecular Immunology, 2019, 105(46-54.

[33] Li X., Luo S., Zhang J., et al. lncRNA H19 Alleviated Myocardial I/RI via Suppressing miR-877-3p/Bcl-2-Mediated Mitochondrial Apoptosis [J]. Mol Ther Nucleic Acids, 2019, 17(297-309.

[34] Zhang X., Cheng L., Xu L., et al. The lncRNA, H19 Mediates the Protective Effect of Hypoxia Postconditioning Against Hypoxia-Reoxygenation Injury to Senescent Cardiomyocytes by Targeting microRNA-29b-3p [J]. SHOCK, 2019, 52(2): 249-56.

[35] Wang J.-X., Zhang X.-J., Li Q., et al. MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD [J]. Circulation Research, 2015, 117(4): 352-63.

[36] Zhang D., Wang B., Ma M., et al. lncRNA HOTAIR Protects Myocardial Infarction Rat by Sponging miR-519d-3p [J]. Journal of Cardiovascular Translational Research, 2019, 12(3): 171-83.

[37] Gao L., Liu Y., Guo S., et al. Circulating Long Noncoding RNA HOTAIR is an Essential Mediator of Acute Myocardial Infarction [J]. Cellular Physiology and Biochemistry, 2017, 44(4): 1497-508.

[38] Gao L., Wang X., Guo S., et al. LncRNA HOTAIR functions as a competing endogenous RNA to upregulate SIRT1 by sponging miR-34a in diabetic cardiomyopathy [J]. Journal of Cellular Physiology, 2019, 234(4): 4944-58.