title: 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.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.forename: Fuminobu
authors.initials: F
authors.lastname: Ishikura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yoshinaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohmoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Yoshino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.forename: Shintaro
authors.initials: S
authors.lastname: Beppu
authors.forename: Michihiko
authors.initials: M
authors.lastname: Tada
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
mesh_terms: D051722:ADAM Proteins; D000072199:ADAM12 Protein; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D006332:Cardiomegaly / Q000188:drug therapy*; D004195:Disease Models, Animal; D019483:Disintegrins / Q000037:antagonists & inhibitors*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006352:Heart Ventricles; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D006973:Hypertension; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000494:pharmacology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction; D013599:Systole; D015533:Transcriptional Activation
chemical_list: D019483:Disintegrins; C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C107086:KB R7785; D008565:Membrane Proteins; D011480:Protease Inhibitors; D000804:Angiotensin II; D010656:Phenylephrine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072199:ADAM12 Protein; D008666:Metalloendopeptidases; D019204:GTP-Binding Proteins; D005998:Glycine