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

Nature Medicine volume 8, pages 35–40 (2002)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan

    Masanori Asakura, Masafumi Kitakaze, Seiji Takashima, Yulin Liao, Koichi Node, Hiroshi Asanuma, Shoji Sanada & Masatsugu Hori

  2. Department of Pathology and Pathophysiology, Osaka University Graduate School of Medicine, Osaka, Japan

    Michihiko Tada

  3. Department of Medical Information Science, Osaka University Graduate School of Medicine, Osaka, Japan

    Yasushi Matsumura & Hiroshi Takeda

  4. Department of Biochemistry, School of Allied Health Science, Osaka University Faculty of Medicine, Osaka, Japan

    Shigeki Higashiyama

  5. Department of Echocardiography, School of Allied Health Science, Osaka University Faculty of Medicine, Osaka, Japan

    Fuminobu Ishikura & Shintaro Beppu

  6. Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan

    Hiroshi Ishiguro

  7. Nippon Organon K.K., Osaka, Japan

    Tsuyoshi Yoshinaka, Hiroshi Ohmoto & Kohichiro Yoshino

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  1. Masanori Asakura
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Correspondence to Seiji Takashima or Shigeki Higashiyama.

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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

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