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- Title
Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy.
- Authors
Asakura, Masanori; Kitakaze, Masafumi; Takashima, Seiji; Liao, Yulin; Ishikura, Fuminobu; Yoshinaka, Tsuyoshi; Ohmoto, Hiroshi; Node, Koichi; Yoshino, Kohichiro; Ishiguro, Hiroshi; Asanuma, Hiroshi; Sanada, Shoji; Matsumura, Yasushi; Takeda, Hiroshi; Beppu, Shintaro; Tada, Michihiko; Hori, Masatsugu; Higashiyama, Shigeki
- 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.
- Publication
Nature medicine, 2002, Vol 8, Issue 1, p35
- ISSN
1078-8956
- Publication type
Journal Article
- DOI
10.1038/nm0102-35