Skip to main content
SpringerLink
Log in

Functional profiling of human atrial and ventricular gene expression

  • Cardiovascular System
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The purpose of our investigation was to identify the transcriptional basis for ultrastructural and functional specialization of human atria and ventricles. Using exploratory microarray analysis (Affymetrix U133A+B), we detected 11,740 transcripts expressed in human heart, representing the most comprehensive report of the human myocardial transcriptome to date. Variation in gene expression between atria and ventricles accounted for the largest differences in this data set, as 3.300 and 2.974 transcripts showed higher expression in atria and ventricles, respectively. Functional classification based on Gene Ontology identified chamber-specific patterns of gene expression and provided molecular insights into the regional specialization of cardiomyocytes, correlating important functional pathways to transcriptional activity: Ventricular myocytes preferentially express genes satisfying contractile and energetic requirements, while atrial myocytes exhibit specific transcriptional activities related to neurohumoral function. In addition, several pro-fibrotic and apoptotic pathways were concentrated in atrial myocardium, substantiating the higher susceptibility of atria to programmed cell death and extracellular matrix remodelling observed in human and experimental animal models of heart failure. Differences in transcriptional profiles of atrial and ventricular myocardium thus provide molecular insights into myocardial cell diversity and distinct region-specific adaptations to physiological and pathophysiological conditions. Moreover, as major functional classes of atrial- and ventricular-specific transcripts were common to human and murine myocardium, an evolutionarily conserved chamber-specific expression pattern in mammalian myocardium is suggested.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Al Shahrour F, Diaz-Uriarte R, Dopazo J (2004) FatiGO: a web tool for finding significant associations of gene ontology terms with groups of genes. Bioinformatics 20:578–580

    Article  CAS  PubMed  Google Scholar 

  2. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. Nat Genet 25:25–29

    Article  CAS  PubMed  Google Scholar 

  3. Barrans JD, Ip J, Lam CW, Hwang IL, Dzau VJ, Liew CC (2003) Chromosomal distribution of the human cardiovascular transcriptome. Genomics 81:519–524

    Article  CAS  PubMed  Google Scholar 

  4. Barth AS, Merk S, Arnoldi E, Zwermann L, Kloos P, Gebauer M, Steinmeyer K, Bleich M, Kääb S, Hinterseer M, Kartmann H, Kreuzer E, Dugas M, Steinbeck G, Nabauer M (2005) Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature. Circ Res (In Press)

    Google Scholar 

  5. Baumer AT, Schumann C, Cremers B, Itter G, Linz W, Jockenhovel F, Böhm M (2002) Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide. J Appl Physiol 92:1058–1063

    CAS  PubMed  Google Scholar 

  6. Bruneau BG, Logan M, Davis N, Levi T, Tabin CJ, Seidman JG, Seidman CE (1999) Chamber-specific cardiac expression of Tbx5 and heart defects in Holt-Oram syndrome. Dev Biol 211:100–108

    Article  CAS  PubMed  Google Scholar 

  7. Bussey KJ, Kane D, Sunshine M, Narasimhan S, Nishizuka S, Reinhold WC, Zeeberg B, Ajay W, Weinstein JN (2003) MatchMiner: a tool for batch navigation among gene and gene product identifiers. Gen Biol 4:R27

    Article  Google Scholar 

  8. Feng JL, Wible B, Li GR, Wang ZG, Nattel S (1997) Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K+ current in cultured adult human atrial myocytes. Circ Res 80:572–579

    CAS  PubMed  Google Scholar 

  9. Forbes MS, Vanniel EE, Purdyramos SI (1990) The atrial myocardial cells of mouse heart—a structural and stereological study. J Struct Biol 103:266–279

    Article  CAS  PubMed  Google Scholar 

  10. Franco D, Lamers WH, Moorman AFM (1998) Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model. Cardiovasc Res 38:25–53

    Article  CAS  PubMed  Google Scholar 

  11. Gentleman R, Carey VJ (2003) Visualization and annotation of genomic experiments. Springer, Berlin Heidelberg New York

    Google Scholar 

  12. Hanna N, Cardin S, Leung TK, Nattel S (2004) Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure. Cardiovasc Res 63:236–244

    Article  CAS  PubMed  Google Scholar 

  13. Holubarsch C, Schmidt-Schweda S, Knorr A, Duis J, Pieske B, Ruf T, Fasol R, Hasenfuss G, Just H (1994) Functional significance of angiotensin receptors in human myocardium—significant differences between atrial and ventricular myocardium. Eur Heart J 15:88–91

    CAS  PubMed  Google Scholar 

  14. Ihaka R, Gentleman R (1996) R: a language for data analysis and graphics. J Comput Graph Stat 5:299–314

    Google Scholar 

  15. Irizarry RA, Gautier CL (2003) The analysis of gene expression data: methods and software. Springer, Berlin Heidelberg New York

    Google Scholar 

  16. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264

    Article  PubMed  Google Scholar 

  17. Jones LR, Field LJ (1993) Residues 2–25 of phospholamban are insufficient to inhibit Ca2+ transport ATPase of cardiac sarcoplasmic-reticulum. J Biol Chem 268:11486–11488

    CAS  PubMed  Google Scholar 

  18. Kääb S, Barth AS, Margerie D, Dugas M, Gebauer M, Zwermann L, Merk S, Pfeufer A, Steinmeyer K, Bleich M, Kreuzer E, Steinbeck G, Nabauer M. (2004) Global gene expression in human myocardium-oligonucleotide microarray analysis of regional diversity and transcriptional regulation in heart failure. J Mol Med 82:308–316

    Article  PubMed  Google Scholar 

  19. Kaynak B, von Heydebreck A, Mebus S, Seelow D, Hennig S, Vogel J, Sperling HP, Pregla R, Alexi-Meskishvili V, Hetzer R, Lange PE, Vingron M, Lehrach H, Sperling S (2003) Genome-wide array analysis of normal and malformed human hearts. Circulation 107:2467–2474

    Article  PubMed  Google Scholar 

  20. Kurabayashi M, Komuro I, Tsuchimochi H, Takaku F, Yazaki Y (1988) Molecular cloning and characterization of human atrial and ventricular myosin alkali light chain cDNA clones. J Biol Chem 263:13930–13936

    CAS  PubMed  Google Scholar 

  21. Legato MJ (1973) Ultrastructure of the atria, ventricular, and Purkinje cell, with special reference to the genesis of arrhythmias. Circulation 46:178–189

    Google Scholar 

  22. Lesage F, Lazdunski M (2000) Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol 279:F793–F801

    CAS  Google Scholar 

  23. Liu GY, Loraine AE, Shigeta R, Cline M, Cheng J, Valmeekam V, Sun S, Kulp D, Siani-Rose MA (2003) NetAffx: affymetrix probesets and annotations. Nucleic Acids Res 31:82–86

    Article  CAS  PubMed  Google Scholar 

  24. Minamisawa S, Wang Y, Chen J, Ishikawa Y, Chien KR, Matsuoka R (2003) Atrial chamber-specific expression of sarcolipin is regulated during development and hypertrophic remodeling. J Biol Chem 278:9570–9575

    Article  CAS  PubMed  Google Scholar 

  25. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:e36

    Article  PubMed  Google Scholar 

  26. Phillips HM, Murdoch JN, Chaudhry B, Copp AJ, Henderson DJ (2005) Vangl2 acts via RhoA signaling to regulate polarized cell movements during development of the proximal outflow tract. Circ Res 96:292–299

    Article  CAS  PubMed  Google Scholar 

  27. Piper HM, Isenberg G (1989) Isolated cardiac myocytes. CRC Press, Boca Raton

    Google Scholar 

  28. Rajeevan MS, Ranamukhaarachchi DG, Vernon SD, Unger ER (2001) Use of real-time quantitative PCR to validate the results of cDNA array and differential display PCR technologies. Methods 25:443–451

    Article  CAS  PubMed  Google Scholar 

  29. Romppanen H, Marttila M, Magga J, Vuolteenaho O, Kinnunen P, Szokodi I, Ruskoaho H (1997) Adrenomedullin gene expression in the rat heart is stimulated by acute pressure overload: blunted effect in experimental hypertension. Endocrinology 138:2636–2639

    Article  CAS  PubMed  Google Scholar 

  30. Small EM, Krieg PA (2004) Molecular regulation of cardiac chamber-specific gene expression. Trends Cardiovasc Med 14:13–18

    Article  CAS  PubMed  Google Scholar 

  31. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100:9440–9445

    Article  CAS  PubMed  MathSciNet  Google Scholar 

  32. Sturn A, Quackenbush J, Trajanoski Z (2002) Genesis: cluster analysis of microarray data. Bioinformatics 18:207–208

    Article  CAS  PubMed  Google Scholar 

  33. Tabibiazar R, Wagner RA, Liao A, Quertermous T (2003) Transcriptional profiling of the heart reveals chamber-specific gene expression patterns. Circ Res 93:1193–1201

    Article  CAS  PubMed  Google Scholar 

  34. Tsubakihara M, Williams NK, Keogh A, dos Remedios CG (2004) Comparison of gene expression between left atria and left ventricles from non-diseased humans. Proteomics 4:261–270

    Article  CAS  PubMed  Google Scholar 

  35. Wang Z, Yue L, White M, Pelletier G, Nattel S (1998) Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. Circulation 98:2422–2428

    CAS  PubMed  Google Scholar 

  36. Zhao Z, Rivkees SA (2004) Rho-associated kinases play a role in endocardial cell differentiation and migration. Dev Biol 275:183–191

    Article  CAS  PubMed  Google Scholar 

  37. Zhao XS, Gallardo TD, Lin L, Schageman JJ, Shohet RV (2002) Transcriptional mapping and genomic analysis of the cardiac atria and ventricles. Physiol Genomics 12:53–60

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Prof. B. Reichart and his colleagues for providing myocardial tissue specimens. Special thanks are due to H. Kartmann for excellent technical assistance with RT-PCR experiments. This study was supported partly by a grant of the Bundesministerium für Bildung und Forschung (BMBF-grant 01GS0109; S.K., A.P., M.N., G.S.) supporting the German National Genome Research Network (NGFN) and a grant from the scientific editorial board of the Münchner Medizinische Wochenschrift (A.S.B.). Data was generated and analysed in the framework of a research collaboration with Aventis Pharma Deutschland GmbH.

Author information

Authors and Affiliations

  1. Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Marchioninistrasse 15, 81377, Munich, Germany

    Andreas S. Barth, Elisabeth Arnoldi, Ludwig Zwermann, Patrick Kloos, Stefan Kääb, Gerhard Steinbeck & Michael Nabauer

  2. Department of Medical Informatics, Biometrics and Epidemiology (IBE), Ludwig-Maximilians-University, Munich, Germany

    Sylvia Merk & Martin Dugas

  3. Aventis Pharma Deutschland GmbH, Frankfurt am Main, Germany

    Mathias Gebauer, Klaus Steinmeyer & Markus Bleich

  4. Institute of Physiology, Christian-Albrechts-University, Kiel, Germany

    Markus Bleich

  5. Institute of Human Genetics, Technical University Munich and GSF, Neuherberg, Germany

    Arne Pfeufer

  6. Department of Cardiac Surgery, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany

    Peter Überfuhr

Authors
  1. Andreas S. Barth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvia Merk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisabeth Arnoldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ludwig Zwermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick Kloos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mathias Gebauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Klaus Steinmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Markus Bleich
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Kääb
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Arne Pfeufer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter Überfuhr
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Dugas
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gerhard Steinbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Michael Nabauer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas S. Barth.

Additional information

This manuscript contains part of Elisabeth Arnoldi’s doctoral thesis, in preparation at the Medical Faculty of the Ludwig-Maximilians-University, Munich, Germany

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barth, A.S., Merk, S., Arnoldi, E. et al. Functional profiling of human atrial and ventricular gene expression. Pflugers Arch - Eur J Physiol 450, 201–208 (2005). https://doi.org/10.1007/s00424-005-1404-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-005-1404-8

Keywords

Search

Navigation