Skip to main content
SpringerLink
Log in

Identification of miR-143 as a Major Contributor for Human Stenotic Aortic Valve Disease

  • Original Article
  • Published:
Journal of Cardiovascular Translational Research Aims and scope Submit manuscript

Abstract

Calcification of aortic valves leads to aortic stenosis mainly in elderly individuals, but the underlying molecular mechanisms are still not understood. Here, we studied microRNA (miR, miRNA) expression and function in healthy and stenotic human aortic valves. We identified miR-21, miR-24, and miR-143 to be highly upregulated in stenotic aortic valves. Using luciferase reporter systems, we found direct binding of miR-143 to the 3′UTR region of the matrix gla protein (MGP), which in turn is a key factor to sustain homeostasis in aortic valves. In subsequent experiments, we demonstrated a therapeutic potential of miRNA regulation during calcification in cardiac valvular interstitial cells. Collectively, our data provide evidence that deregulated miR expression contributes to the development of stenotic valve disease and thus form novel therapeutic opportunities of this severe cardiovascular disease.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

miRNA, miR:

microRNA

AS:

Aortic stenosis

AVIC:

Aortic valve interstitial cells

References

  1. Thaden, J. J., Nkomo, V. T., & Enriquez-Sarano, M. (2014). The global burden of aortic stenosis. Progress in Cardiovascular Diseases, 56, 565–571.

    Article  Google Scholar 

  2. Carabello, B. A. (2013). Introduction to aortic stenosis. Circulation Research, 113, 179–185.

    Article  CAS  Google Scholar 

  3. Bach, D. S. (2011). Prevalence and characteristics of unoperated patients with severe aortic stenosis. The Journal of Heart Valve Disease, 20, 284–291.

    PubMed  Google Scholar 

  4. Park, S. J., Enriquez-Sarano, M., Chang, S. A., Choi, J. O., Lee, S. C., Park, S. W., Kim, D. K., Jeon, E. S., & Oh, J. K. (2013). Hemodynamic patterns for symptomatic presentations of severe aortic stenosis. JACC: Cardiovascular Imaging, 6, 137–146.

    PubMed  Google Scholar 

  5. Bonow, R. O., Carabello, B. A., Chatterjee, K., de Leon, A. C., Jr., Faxon, D. P., Freed, M. D., Gaasch, W. H., Lytle, B. W., Nishimura, R. A., O’Gara, P. T., O’Rourke, R. A., Otto, C. M., Shah, P. M., Shanewise, J. S., & American College of Cardiology/American Heart Association Task Force on Practice Guidelines. (2008). 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American heart association task force on practice guidelines (writing committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, and society of thoracic surgeons. Journal of the American College of Cardiology, 52, e1–e142.

  6. Lewis, B. P., Burge, C. B., & Bartel, D. P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell., 120, 15–20.

    Article  CAS  Google Scholar 

  7. Sheehan D, Hrapchak B (1980) Theory and practice of histotechnology. Battelle Press, Ohio; 2nd Ed: 226–227.

  8. Thum, T., Gross, C., Fiedler, J., Fischer, T., Kissler, S., Bussen, M., Galuppo, P., Just, S., Rottbauer, W., Frantz, S., Castoldi, M., Soutschek, J., Koteliansky, V., Rosenwald, A., Basson, M. A., Licht, J. D., Pena, J. T., Rouhanifard, S. H., Muckenthaler, M. U., Tuschl, T., Martin, G. R., Bauersachs, J., & Engelhardt, S. (2008). MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature, 456, 980–984.

    Article  CAS  Google Scholar 

  9. Fiedler, J., Jazbutyte, V., Kirchmaier, B. C., Gupta, S. K., Lorenzen, J., Hartmann, D., Galuppo, P., Kneitz, S., Pena, J. T., Sohn-Lee, C., Loyer, X., Soutschek, J., Brand, T., Tuschl, T., Heineke, J., Martin, U., Schulte-Merker, S., Ertl, G., Engelhardt, S., Bauersachs, J., & Thum, T. (2011). MicroRNA-24 regulates vascularity after myocardial infarction. Circulation, 124, 720–730.

    Article  CAS  Google Scholar 

  10. Cordes, K. R., Sheehy, N. T., White, M. P., Berry, E. C., Morton, S. U., Muth, A. N., Lee, T. H., Miano, J. M., Ivey, K. N., & Srivastava, D. (2009). miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature., 460, 705–710.

    Article  CAS  Google Scholar 

  11. Boettger, T., Beetz, N., Kostin, S., Schneider, J., Kruger, M., Hein, L., & Braun, T. (2009). Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. The Journal of Clinical Investigation, 119, 2634–2647.

    Article  CAS  Google Scholar 

  12. Luo, G., Ducy, P., McKee, M. D., Pinero, G. J., Loyer, E., Behringer, R. R., & Karsenty, G. (1997). Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature., 386, 78–81.

    Article  CAS  Google Scholar 

  13. Pillai, I. C. L., Li, S., Romay, M., Lam, L., Lu, Y., Huang, J., Dillard, N., Zemanova, M., Rubbi, L., Wang, Y., Lee, J., Xia, M., Liang, O., Xie, Y. H., Pellegrini, M., Lusis, A. J., & Deb, A. (2017). Cardiac fibroblasts adopt osteogenic fates and can be targeted to attenuate pathological heart calcification. Cell Stem Cell, 20, 218–232.e5.

    Article  CAS  Google Scholar 

  14. Dweck, M. R., Jones, C., Joshi, N. V., Fletcher, A. M., Richardson, H., White, A., Marsden, M., Pessotto, R., Clark, J. C., Wallace, W. A., Salter, D. M., McKillop, G., van Beek, E. J., Boon, N. A., Rudd, J. H., & Newby, D. E. (2012). Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis. Circulation, 125, 76–86.

    Article  CAS  Google Scholar 

  15. Song, R., Fullerton, D. A., Ao, L., Zhao, K. S., & Meng, X. (2017). An epigenetic regulatory loop controls pro-osteogenic activation by TGF-beta1 or bone morphogenetic protein 2 in human aortic valve interstitial cells. The Journal of Biological Chemistry, 292, 8657–8666.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Robert Ramm (Hannover Medical School) for establishment of porcine valve interstitial cell isolation. Da-Hee Park acknowledges support from IFB-Tx and Hannover Biomedical Research School (Strucmed program) at Hannover Medical School.

Author information

Author notes

  1. Jan Fiedler, Da-Hee Park and Lisa Hobuß contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Jan Fiedler, Da-Hee Park, Lisa Hobuß, Angelika Pfanne, Annette Just, Saskia Mitzka & Thomas Thum

  2. Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany

    Da-Hee Park, Annette Just & Thomas Thum

  3. Department of Nephrology, Hannover Medical School, Hannover, Germany

    Parnian Kalbasi Anaraki & Inna Dumler

  4. Department of Cardiology, Klinikum Vest, Recklinghausen, Germany

    Frank Weidemann

  5. Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Hannover, Germany

    Andres Hilfiker

  6. National Heart and Lung Institute, Imperial College London, London, UK

    Thomas Thum

  7. REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany

    Thomas Thum

Authors
  1. Jan Fiedler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Da-Hee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa Hobuß
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Parnian Kalbasi Anaraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angelika Pfanne
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annette Just
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Saskia Mitzka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Inna Dumler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Frank Weidemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andres Hilfiker
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Thum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jan Fiedler or Thomas Thum.

Ethics declarations

Conflict of Interest

The authors disclose support from DFG (KFO311 to TT) and EraNet Expert (to TT). TT and JF have filed patents in the field of cardiovascular miRNA diagnostics and therapeutics. TT is founder of Cardior Pharmaceuticals GmbH.

Human Subjects/Informed Consent Statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. Aortic valve samples were obtained from patients undergoing aortic valve replacement in the University Hospital Würzburg approved by ethics committee (study number 111/03 from 09/2003).

Additional information

Associate Editor Adrian Chester oversaw the review of this article

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fiedler, J., Park, DH., Hobuß, L. et al. Identification of miR-143 as a Major Contributor for Human Stenotic Aortic Valve Disease. J. of Cardiovasc. Trans. Res. 12, 447–458 (2019). https://doi.org/10.1007/s12265-019-09880-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12265-019-09880-7

Keywords

Search

Navigation