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Molecular Medicine

, Volume 17, Issue 11–12, pp 1365–1373 | Cite as

Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study

  • Lasse Folkersen
  • Dick Wågsäter
  • Valentina Paloschi
  • Veronica Jackson
  • Johan Petrini
  • Sanela Kurtovic
  • Shohreh Maleki
  • Maria J. Eriksson
  • Kenneth Caidahl
  • Anders Hamsten
  • Jean-Baptiste Michel
  • Jan Liska
  • Anders Gabrielsen
  • Anders Franco-Cereceda
  • Per Eriksson
Research Article

Abstract

Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (<4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.

Notes

Acknowledgments

This study was supported by the Swedish Research Council (12660), the Stockholm County Council, the Swedish Heart-Lung foundation, the European Commission (FAD, Health-F2-2008-200647), DASTI (Danish Agency for Science, Technology and Innovation) and a donation by Fredrik Lundberg.

Supplementary material

10020_2011_17111365_MOESM1_ESM.pdf (1.9 mb)
Supplementary material, approximately 1925 KB.

References

  1. 1.
    El-Hamamsy I, Yacoub MH. (2009) Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat. Rev. Cardiol. 6:771–86.CrossRefGoogle Scholar
  2. 2.
    Nkomo VT, et al. (2003) Bicuspid aortic valve associated with aortic dilatation: a community-based study. Arterioscler. Thromb. Vasc. Biol. 23:351–6.CrossRefGoogle Scholar
  3. 3.
    Jackson V, et al. (2011) Bicuspid aortic valve leaflet morphology in relation to aortic root morphology: a study of 300 patients undergoing open-heart surgery. Eur. J. Cardiothorac. Surg. 40:e118–24.PubMedGoogle Scholar
  4. 4.
    Siu SC, Silversides CK. (2010) Bicuspid aortic valve disease. J. Am. Coll. Cardiol. 55:2789–800.CrossRefGoogle Scholar
  5. 5.
    Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. (2004) Bicuspid aortic valve is heritable. J. Am. Coll. Cardiol. 44:138–43.CrossRefGoogle Scholar
  6. 6.
    Ramirez F, Dietz HC. (2007) Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr. Opin. Genet. Dev. 17:252–8.CrossRefGoogle Scholar
  7. 7.
    Loeys BL, et al. (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N. Engl. J. Med. 355:788–98.CrossRefGoogle Scholar
  8. 8.
    Hope MD, et al. (2010) Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns. Radiology. 255:53–61.CrossRefGoogle Scholar
  9. 9.
    Yasuda H, et al. (2003) Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve. Circulation. 108:291–4.CrossRefGoogle Scholar
  10. 10.
    Folkersen L, et al. (2009) Endogenous control genes in complex vascular tissue samples. BMC Genomics. 10:516.CrossRefGoogle Scholar
  11. 11.
    Storey JD, Tibshirani R. (2003) Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. U. S. A. 100:9440–5.CrossRefGoogle Scholar
  12. 12.
    Luo W, Friedman MS, Shedden K, Hankenson KD, Woolf PJ. (2009) GAGE: generally applicable gene set enrichment for pathway analysis. B.M.C. Bioinformatics. 10:161.CrossRefGoogle Scholar
  13. 13.
    Schmid FX, et al. (2003) Ascending aortic aneurysm associated with bicuspid and tricuspid aortic valve: involvement and clinical relevance of smooth muscle cell apoptosis and expression of cell death-initiating proteins. Eur. J. Cardiothorac. Surg. 23:537–43.CrossRefGoogle Scholar
  14. 14.
    Majumdar R, et al. (2007) Elevated expressions of osteopontin and tenascin C in ascending aortic aneurysms are associated with trileaflet aortic valves as compared with bicuspid aortic valves. Cardiovasc. Pathol. 16:144–50.CrossRefGoogle Scholar
  15. 15.
    Fedak PW, et al. (2003) Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J. Thorac. Cardiovasc. Surg. 126:797–806.CrossRefGoogle Scholar
  16. 16.
    Phillippi JA, et al. (2009) Basal and oxidative stress-induced expression of metallothionein is decreased in ascending aortic aneurysms of bicuspid aortic valve patients. Circulation. 119:2498–506.CrossRefGoogle Scholar
  17. 17.
    Wooten EC, et al. (2010) Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve. P. L. o. S. ONE. 5:e8830.CrossRefGoogle Scholar
  18. 18.
    Paloschi V, et al. (2011) Impaired splicing of fibronectin is associated with thoracic aortic aneurysm formation in patients with bicuspid aortic valve. Arterioscler. Thromb. Vasc. Biol. 31:691–7.CrossRefGoogle Scholar
  19. 19.
    Wagsater D, et al. (2008) ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis. 196:514–22.CrossRefGoogle Scholar
  20. 20.
    Meng H, et al. (2010) Low density lipoprotein receptor-related protein-1 (LRP1) regulates thrombospondin-2 (TSP2) enhancement of Notch3 signaling. J. Biol. Chem. 285:23047–55.CrossRefGoogle Scholar
  21. 21.
    Jager S, et al. (2004) Role for Rab7 in maturation of late autophagic vacuoles. J. Cell Sci. 117:4837–48.CrossRefGoogle Scholar
  22. 22.
    Kennard S, Liu H, Lilly B. (2008) Transforming growth factor-beta (TGF-1) down-regulates Notch3 in fibroblasts to promote smooth muscle gene expression. J. Biol. Chem. 283:1324–33.CrossRefGoogle Scholar
  23. 23.
    Suzuki HI, Kiyono K, Miyazono K. (2010) Regulation of autophagy by transforming growth factor-beta (TGFbeta) signaling. Autophagy. 6:645–7.CrossRefGoogle Scholar
  24. 24.
    Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. (2008) LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 88:887–918.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Lasse Folkersen
    • 1
    • 2
  • Dick Wågsäter
    • 1
  • Valentina Paloschi
    • 1
  • Veronica Jackson
    • 3
  • Johan Petrini
    • 4
  • Sanela Kurtovic
    • 1
  • Shohreh Maleki
    • 1
  • Maria J. Eriksson
    • 4
  • Kenneth Caidahl
    • 4
  • Anders Hamsten
    • 1
  • Jean-Baptiste Michel
    • 5
  • Jan Liska
    • 3
  • Anders Gabrielsen
    • 2
  • Anders Franco-Cereceda
    • 3
  • Per Eriksson
    • 1
  1. 1.Atherosclerosis Research Unit, Center for Molecular Medicine, CMM L8:03Karolinska University Hospital SolnaStockholmSweden
  2. 2.Experimental Cardiovascular Research Unit, Center for Molecular Medicine, Department of MedicineKarolinska InstitutetStockholmSweden
  3. 3.Cardiothoracic Surgery Unit, Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
  4. 4.Clinical Physiology, Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
  5. 5.INSERM U698ParisFrance

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