Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: Metalloproteinase inhibitors as a new therapy

Abstract

G-protein–coupled receptor (GPCR) agonists are well-known inducers of cardiac hypertrophy. We found that the shedding of heparin-binding epidermal growth factor (HB-EGF) resulting from metalloproteinase activation and subsequent transactivation of the epidermal growth factor receptor occurred when cardiomyocytes were stimulated by GPCR agonists, leading to cardiac hypertrophy. A new inhibitor of HB-EGF shedding, KB-R7785, blocked this signaling. We cloned a disintegrin and metalloprotease 12 (ADAM12) as a specific enzyme to shed HB-EGF in the heart and found that dominant-negative expression of ADAM12 abrogated this signaling. KB-R7785 bound directly to ADAM12, suggesting that inhibition of ADAM12 blocked the shedding of HB-EGF. In mice with cardiac hypertrophy, KB-R7785 inhibited the shedding of HB-EGF and attenuated hypertrophic changes. These data suggest that shedding of HB-EGF by ADAM12 plays an important role in cardiac hypertrophy, and that inhibition of HB-EGF shedding could be a potent therapeutic strategy for cardiac hypertrophy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Effects of KB-R7785 and HB-EGF neutralizing antibody on EGFR transactivation and protein synthesis induced by GPCR agonists in cardiomyocytes.
Figure 2: Involvement of ADAM12 in EGFR transactivation by GPCR agonists.
Figure 3: KB-R7785 attenuates left-ventricular hypertrophy due to pressure overload and inhibits shedding of proHB-EGF in vivo.

Similar content being viewed by others

References

  1. Katz, A.M. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N. Engl. J. Med. 322, 100–110 (1990).

    Article  CAS  Google Scholar 

  2. Levy, D., Garrison, R.J., Savage, D.D., Kannel, W.B. & Castelli, W.P. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N. Engl. J. Med 322, 1561–1566 (1990).

    Article  CAS  Google Scholar 

  3. Simpson, P., McGrath, A. & Savion, S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ. Res. 51, 787–801 (1982).

    Article  CAS  Google Scholar 

  4. Ito, H. et al. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ. Res. 69, 209–215 (1991).

    Article  CAS  Google Scholar 

  5. Sadoshima, J., Xu, Y., Slayter, H.S. & Izumo, S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75, 977–984 (1993).

    Article  CAS  Google Scholar 

  6. Schmieder, R.E., Martus, P. & Klingbeil, A. Reversal of left ventricular hypertrophy in essential hypertension. A meta-analysis of randomized double-blind studies. JAMA 275, 1507–1513 (1996).

    Article  CAS  Google Scholar 

  7. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N. Engl. J. Med. 316, 1429–1435 (1987).

  8. Chien, K.R. et al. Transcriptional regulation during cardiac growth and development. Annu. Rev. Physiol. 55, 77–95 (1993).

    Article  CAS  Google Scholar 

  9. Sadoshima, J. & Izumo, S. The cellular and molecular response of cardiac myocytes to mechanical stress. Annu. Rev. Physiol. 59, 551–571 (1997).

    Article  CAS  Google Scholar 

  10. Daub, H., Weiss, F.U., Wallasch, C. & Ullrich, A. Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379, 557–560 (1996).

    Article  CAS  Google Scholar 

  11. Tsai, W., Morielli, A.D. & Peralta, E.G. The m1 muscarinic acetylcholine receptor transactivates the EGF receptor to modulate ion channel activity. EMBO J. 16, 4597–4605 (1997).

    Article  CAS  Google Scholar 

  12. Zwick, E. et al. Critical role of calcium-dependent epidermal growth factor receptor transactivation in PC12 cell membrane depolarization and bradykinin signaling. J. Biol. Chem. 272, 24767–24770 (1997).

    Article  CAS  Google Scholar 

  13. Eguchi, S. et al. Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. J. Biol. Chem. 273, 8890–8896 (1998).

    Article  CAS  Google Scholar 

  14. Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).

    Article  CAS  Google Scholar 

  15. Spinale, F.G. et al. Matrix metalloproteinase inhibition during the development of congestive heart failure: effects on left ventricular dimensions and function. Circ. Res. 85, 364–376 (1999).

    Article  CAS  Google Scholar 

  16. Tokumaru, S. et al. Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing. J. Cell Biol. 151, 209–220 (2000)

    Article  CAS  Google Scholar 

  17. Goishi, K. et al. Phorbol ester induces the rapid processing of cell surface heparin-binding EGF-like growth factor: Conversion from juxtacrine to paracrine growth factor activity. Mol. Biol. Cell 6, 967–980 (1995).

    Article  CAS  Google Scholar 

  18. Izumi, Y. et al. A metalloprotease-disintegrin, MDC9/meltrin-γ/ADAM9 and PKCδ are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 17, 7260–7272 (1998).

    Article  CAS  Google Scholar 

  19. Moss, M.L. et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature 385, 733–736 (1997).

    Article  CAS  Google Scholar 

  20. Friddle, C.J., Koga, T., Rubin, E.M. & Bristow, J. Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc. Natl. Acad. Sci. USA 97, 6745–6750 (2000).

    Article  CAS  Google Scholar 

  21. Saadane, N., Alpert, L. & Chalifour, L.E. Expression of immediate early genes, GATA-4, and Nkx-2.5 in adrenergic-induced cardiac hypertrophy and during regression in adult mice. Br. J. Pharmacol. 127, 1165–1176 (1999).

    Article  CAS  Google Scholar 

  22. Higashiyama, S., Lau, K., Besner, G., Abraham, J. A. & Klagsbrun, M. Structure of heparin-binding EGF-like growth factor: Multiple forms, primary structure, and glycosylation of the mature protein. J. Biol. Chem. 267, 6205–6212 (1992).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J.A. Abraham for helpful comments and advice; and J. Yamada, A. Ohno, T. Fukushima, A. Ogai and S. Mori for technical assistance. This study is supported by Grant-in-aid for Scientific Research (No. 09281102, 12370153 and 12877107) from the Ministry of Education, Science and Culture, Japan.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Seiji Takashima or Shigeki Higashiyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Asakura, M., Kitakaze, M., Takashima, S. et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: Metalloproteinase inhibitors as a new therapy. Nat Med 8, 35–40 (2002). https://doi.org/10.1038/nm0102-35

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0102-35

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing