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


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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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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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).

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