Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. |
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| Authors: | Masanori Asakura Masafumi Kitakaze Seiji Takashima Yulin Liao Fuminobu Ishikura Tsuyoshi Yoshinaka Hiroshi Ohmoto Koichi Node Kohichiro Yoshino Hiroshi Ishiguro Hiroshi Asanuma Shoji Sanada Yasushi Matsumura Hiroshi Takeda Shintaro Beppu Michihiko Tada Masatsugu Hori Shigeki Higashiyama |
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| Institution: | Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan. |
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| 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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