Construction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveals functional genes in heart failure

Heart failure (HF) is a principal cause of morbidity and mortality worldwide, affecting an estimated 38 million people. Although significant progress has been made with respect to the underlying molecular mechanisms, the role of the competing endogenous RNA (ceRNA) network in the pathogenesis of HF remains largely unknown. In this study, an HF-associated ceRNA network was constructed based on the differentially expressed long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and mRNAs obtained, respectively, from the GSE77399, GSE104150 and GSE84796 datasets. The ceRNA network consisted of 12 lncRNA nodes, 43 miRNA nodes, 343 mRNA nodes and 530 edges. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated that the ceRNA network was primarily enriched in the immune response, inflammatory response and T cell and B cell receptor signaling pathways. In addition, three lncRNAs (growth arrest specific 5, taurine upregulated 1 and HOX transcript antisense RNA) and three miRNAs [hsa-miRNA (miR)-26b-5p, hsa-miR-8485 and hsa-miR-940] with higher node degrees compared with other genes were selected as hub nodes. The expression of hub nodes in patients with HF was verified by reverse transcription-quantitative polymerase chain reaction analysis. The present study provided further insights into the important roles of the ceRNA network in HF development, and indicated the potential use of these hub nodes as diagnostic biomarkers and therapeutic targets.

[1]  Paola Fuschi,et al.  Long noncoding RNA dysregulation in ischemic heart failure , 2016, Journal of Translational Medicine.

[2]  Dong Wang,et al.  Competing endogenous RNA networks in human cancer: hypothesis, validation, and perspectives , 2016, Oncotarget.

[3]  Hsien-Da Huang,et al.  miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions , 2017, Nucleic Acids Res..

[4]  I. Ng,et al.  Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications , 2018, Nature Reviews Gastroenterology & Hepatology.

[5]  Chun-mei Li,et al.  LncRNA TUG1 serves an important role in hypoxia-induced myocardial cell injury by regulating the miR-145-5p-Binp3 axis , 2017, Molecular medicine reports.

[6]  E. Braunwald The war against heart failure: the Lancet lecture , 2015, The Lancet.

[7]  P. Tontonoz,et al.  Long Noncoding RNA Discovery in Cardiovascular Disease: Decoding Form to Function , 2018, Circulation research.

[8]  J. Carroll,et al.  Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer , 2018, Oncogene.

[9]  Pei Ma,et al.  Long Noncoding RNA LINC01234 Functions as a Competing Endogenous RNA to Regulate CBFB Expression by Sponging miR-204-5p in Gastric Cancer , 2018, Clinical Cancer Research.

[10]  J. Bauersachs,et al.  Immune mechanisms in heart failure , 2017, European journal of heart failure.

[11]  Jian Wu,et al.  Identification of key genes and pathways in regulating immune-induced diseases of dendritic cells by bioinformatic analysis , 2018, Molecular medicine reports.

[12]  D. Bartel,et al.  lincRNAs: Genomics, Evolution, and Mechanisms , 2013, Cell.

[13]  S. Solomon,et al.  Improving Heart Failure Therapeutics Development in the United States: The Heart Failure Collaboratory. , 2018, Journal of the American College of Cardiology.

[14]  Panayiotis Tsanakas,et al.  DIANA-LncBase v2: indexing microRNA targets on non-coding transcripts , 2015, Nucleic Acids Res..

[15]  S. Zhuang,et al.  HOTAIR functions as a competing endogenous RNA to regulate PTEN expression by inhibiting miR-19 in cardiac hypertrophy , 2017, Molecular and Cellular Biochemistry.

[16]  Y. Tham,et al.  Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets , 2015, Archives of Toxicology.

[17]  C. Murray,et al.  The Global Burden of Ischemic Heart Disease in 1990 and 2010: The Global Burden of Disease 2010 Study , 2014, Circulation.

[18]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[19]  M. Aronovitz,et al.  Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure , 2017, The Journal of experimental medicine.

[20]  P. Shi,et al.  LncRNA GAS5 controls cardiac fibroblast activation and fibrosis by targeting miR-21 via PTEN/MMP-2 signaling pathway. , 2017, Toxicology.

[21]  N. Smart,et al.  Effect of aerobic and resistance training on inflammatory markers in heart failure patients: systematic review and meta-analysis , 2018, Heart Failure Reviews.

[22]  Shuwen Han,et al.  Competitive endogenous RNA in colorectal cancer: A systematic review. , 2018, Gene.

[23]  Lu Gao,et al.  Circulating Long Noncoding RNA HOTAIR is an Essential Mediator of Acute Myocardial Infarction , 2017, Cellular Physiology and Biochemistry.

[24]  P. Little,et al.  Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics. , 2019, Pharmacology & therapeutics.

[25]  M. Maurer,et al.  Pathophysiology of Heart Failure , 2007 .

[26]  Yun Xiao,et al.  Dysregulated long intergenic non-coding RNA modules contribute to heart failure , 2016, Oncotarget.

[27]  Hui Jiang,et al.  Reconstruction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in rheumatoid arthritis. , 2017, Molecular bioSystems.

[28]  Gerasimos S Filippatos,et al.  2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. , 2017, Journal of cardiac failure.

[29]  P. Ponikowski,et al.  Signature of circulating microRNAs in patients with acute heart failure , 2016, European journal of heart failure.

[30]  Eugene Berezikov,et al.  Rodent heart failure models do not reflect the human circulating microRNA signature in heart failure , 2017, PloS one.

[31]  S. Epelman,et al.  Chronic Heart Failure and Inflammation: What Do We Really Know? , 2016, Circulation research.

[32]  J. Fildes,et al.  The immune system and chronic heart failure: is the heart in control? , 2009, Journal of the American College of Cardiology.

[33]  Wang Ma,et al.  ceRNA in cancer: possible functions and clinical implications , 2015, Journal of Medical Genetics.

[34]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[35]  Lan V. Zhang,et al.  Evidence for dynamically organized modularity in the yeast protein–protein interaction network , 2004, Nature.

[36]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[37]  Dandan Liang,et al.  miRNA-940 reduction contributes to human Tetralogy of Fallot development , 2014, Journal of cellular and molecular medicine.

[38]  J. Hou Lecture , 2012 .

[39]  Howard Y. Chang,et al.  Molecular mechanisms of long noncoding RNAs. , 2011, Molecular cell.

[40]  J. Hulot,et al.  Gene therapy for the treatment of heart failure: promise postponed. , 2016, European heart journal.

[41]  Saumya Das,et al.  Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients , 2016, Oncotarget.

[42]  Gerasimos S Filippatos,et al.  2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. , 2017, Journal of the American College of Cardiology.

[43]  Hulun Li,et al.  Inhibition of MicroRNA let-7i Depresses Maturation and Functional State of Dendritic Cells in Response to Lipopolysaccharide Stimulation via Targeting Suppressor of Cytokine Signaling 1 , 2011, The Journal of Immunology.

[44]  C. Bearzi,et al.  Increased BACE1-AS long noncoding RNA and &bgr;-amyloid levels in heart failure , 2017, Cardiovascular research.

[45]  Z. Papp,et al.  Causes and pathophysiology of heart failure with preserved ejection fraction. , 2014, Heart failure clinics.