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Identification of Biomarkers for Schistosoma-Associated Pulmonary Arterial Hypertension Based on RNA-Seq Data of Mouse Whole Lung Tissues

  • Pulmonary Vascular Disease
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Abstract

Background

Pulmonary arterial hypertension (PAH) is a deadly disease, and the molecular mechanism of PAH has not been clarified clearly. The objective of this study was to identify possible biomarkers and explore the potential mechanisms of Schistosoma-induced PAH.

Methods

GSE49114 RNA-Seq data developed from mouse whole lung tissues were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between control samples and schistosomiasis-induced PAH samples were identified by the edgeR software. Gene Ontology (GO) and pathway enrichment analysis of DEGs were performed, followed by metabolic pathway network construction. Moreover, pathways with higher connectivity degrees in the metabolic pathway network were identified.

Results

Totally, 877 up- and 520 downregulated DEGs were screened. The upregulated DEGs such as IL-4 (Interleukin-4) were significantly related with immune system process, transmembrane signaling receptor activity, and signal transducer activity. Downregulated DEGs (i.e., Smad9 (SMAD family member 9), BMPR2 (bone morphogenetic protein type 2 receptor), and Eng (endoglin)) were significantly enriched in signal transducer activity, growth factor binding, and signal transduction. The top 10 metabolic pathways with highest connectivity degree were screened, including leishmaniasis (degree = 26), antigen processing and presentation (degree = 20), hematopoietic cell lineage (degree = 20), chemokine signaling pathway (degree = 18), and JAK–STAT signaling pathway (degree = 18).

Conclusions

Smad9, BMPR2, Eng and IL4, and their relative functions such as signal transduction, signal transducer activity, and immune system process might play important roles in schistosomiasis-induced PAH. Moreover, the interaction of metabolic pathways was critical in the development of schistosomiasis-PAH.

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References

  1. Galiè N (2004) Pulmonary arterial hypertension: epidemiology, Pathobiology, assessment, and therapy. Elsevier, Amsterdam

    Google Scholar 

  2. de Cleva R, Herman P, Pugliese V et al. (2002) Prevalence of pulmonary hypertension in patients with hepatosplenic masonic schistosomiasis–prospective study. Hepato-gastroenterology 50:2028–2030

    Google Scholar 

  3. Butrous G (2014) Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: schistosomiasis and pulmonary arterial hypertension. Ann Thorac Med 9:S38

    Article  PubMed  PubMed Central  Google Scholar 

  4. Humbert M, Sitbon O, Chaouat A et al (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173:1023–1030

    Article  PubMed  Google Scholar 

  5. McLaughlin V (2011) Looking to the future: a new decade of pulmonary arterial hypertension therapy. Eur Respir Rev 20:262–269

    Article  CAS  PubMed  Google Scholar 

  6. Dorfmüller P, Perros F, Balabanian K et al (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22:358–363

    Article  PubMed  Google Scholar 

  7. Morrell NW (2010) Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension. In: Membrane receptors, channels and transporters in pulmonary circulation. Springer, New York, p 251–264

    Chapter  Google Scholar 

  8. Chandra SM, Razavi H, Kim J et al (2011) Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol 31:814–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Graham BB, Chabon J, Kumar R et al (2013) Protective role of IL-6 in vascular remodeling in schistosoma pulmonary hypertension. Am J Respir Cell Mol Biol 49:951–959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tuder RM (2009) Pathology of pulmonary arterial hypertension. In: Seminars in respiratory and critical care medicine. © Thieme Medical Publishers, Stuttgart, p 376–385

    Google Scholar 

  11. Pickrell JK, Marioni JC, Pai AA et al (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464:768–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Marguerat S, Bähler J (2010) RNA-seq: from technology to biology. Cell Mol Life Sci 67:569–579

    Article  CAS  PubMed  Google Scholar 

  13. Graham BB, Chabon J, Gebreab L et al (2013) Transforming growth factor-β signaling promotes pulmonary hypertension caused by Schistosoma mansoni. Circulation 128:1354–1364

    Article  CAS  PubMed  Google Scholar 

  14. Kumar R, Mickael C, Chabon J et al (2015) The causal role of IL-4 and IL-13 in Schistosoma mansoni pulmonary hypertension. Am J Respir Crit Care Med 192:998–1008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barrett T, Troup DB, Wilhite SE et al (2007) NCBI GEO: mining tens of millions of expression profiles—database and tools update. Nucleic Acids Res 35:D760–D765

    Article  CAS  PubMed  Google Scholar 

  16. Sherry S (2012) NCBI SRA Toolkit Technology for Next Generation Sequence Data. In: Plant and Animal Genome XX Conference. Plant and Animal Genome

  17. Joshi NA Fass JN (2011) Sickle: a sliding-window, adaptive, quality-based trimming tool for FastQ files (Version 1.33) [Software]. https://github.com/najoshi/sickle.

  18. Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9:357–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim D, Pertea G, Trapnell C et al (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14:R36

    Article  PubMed  PubMed Central  Google Scholar 

  20. Trapnell C, Williams BA, Pertea G et al (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28:511–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140

    Article  CAS  PubMed  Google Scholar 

  23. Consortium G O (2004) The gene ontology (GO) database and informatics resource. Nucleic Acids Res 32:D258–D261

    Article  Google Scholar 

  24. Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Young MD, Wakefield MJ, Smyth GK et al. (2010) Method gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol 11(2):1

    Article  Google Scholar 

  26. Benjamini Y, Drai D, Elmer G et al (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279–284

    Article  CAS  PubMed  Google Scholar 

  27. Dutta B, Wallqvist A, Reifman J (2012) PathNet: a tool for pathway analysis using topological information. Source Code Biol Med 7:10. doi:10.1186/1751-0473-7-10

    Article  PubMed  PubMed Central  Google Scholar 

  28. Dutta B, Wallqvist A, Reifman J (2012) PathNet: a tool for pathway analysis using topological information. Source Code Biol Med 7(1):1

    Article  Google Scholar 

  29. Yu C, Zavaljevski N, Desai V et al (2011) QuartetS: a fast and accurate algorithm for large-scale orthology detection. Nucleic Acids Res 39:e88. doi:10.1093/nar/gkr308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yu C, Desai V, Cheng L et al (2012) QuartetS-DB: a large-scale orthology database for prokaryotes and eukaryotes inferred by evolutionary evidence. BMC Bioinform 13:143. doi:10.1186/1471-2105-13-143

    Article  Google Scholar 

  31. Malenfant S, Neyron A-S, Paulin R et al (2013) Signal transduction in the development of pulmonary arterial hypertension. Pulmonary circulation 3:278

    Article  PubMed  PubMed Central  Google Scholar 

  32. Miyazono K, Ten Dijke P, Heldin C-H (2000) TGF-β signaling by Smad proteins. Adv Immunol 75:115–157

    Article  CAS  PubMed  Google Scholar 

  33. Runo JR, Vnencak-Jones CL, Prince M et al (2003) Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med 167:889–894

    Article  PubMed  Google Scholar 

  34. Chaouat A, Coulet F, Favre C et al (2004) Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59:446–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Austin ED, Ma L, LeDuc C et al (2012) Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circulation 5:336–343

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Humbert M, Morrell NW, Archer SL et al (2004) Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:S13–S24

    Article  Google Scholar 

  37. Rudarakanchana N, Flanagan JA, Chen H et al (2002) Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 11:1517–1525

    Article  CAS  PubMed  Google Scholar 

  38. Grijelmo C, Rodrigue C, Svrcek M et al (2007) Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells. Cell Signal 19:1722–1732

    Article  CAS  PubMed  Google Scholar 

  39. Massagué J, Chen Y-G (2000) Controlling TGF-β signaling. Genes Develop 14:627–644

    PubMed  Google Scholar 

  40. Graham BB, Kumar R (2009) Schistosomiasis and the Pulmonary Vasculature. Hypertension 1954:S43–S54

    Google Scholar 

  41. Graham BB, Mentink-Kane MM, El-Haddad H et al (2010) Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol 177:1549–1561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pittet J-F, Griffiths MJ, Geiser T et al (2001) TGF-β is a critical mediator of acute lung injury. J Clin Invest 107:1537–1544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Masri FA, Xu W, Comhair SA et al (2007) Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol-Lung Cell Mol Physiol 293:L548–L554

    Article  CAS  PubMed  Google Scholar 

  44. Kisseleva T, Bhattacharya S, Braunstein J et al (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24

    Article  CAS  PubMed  Google Scholar 

  45. Crosby A, Soon E, Jones FM et al (2015) Hepatic shunting of eggs and pulmonary vascular remodeling in Bmpr2+/− mice with schistosomiasis. Am J Respir Crit Care Med 192:1355–1365

    Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Lei Li.

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Sun, Y., Lin, X. & Li, L. Identification of Biomarkers for Schistosoma-Associated Pulmonary Arterial Hypertension Based on RNA-Seq Data of Mouse Whole Lung Tissues. Lung 195, 377–385 (2017). https://doi.org/10.1007/s00408-017-9999-z

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  • DOI: https://doi.org/10.1007/s00408-017-9999-z

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