[Membrane-anchored heparin-binding EGF-like growth factor processing by ADAM12 in cardiac hypertrophy].
G-protein coupled receptor(GPCR) agonists are well-known inducers of cardiac hypertrophy. We found that the shedding of HB-EGF via 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.
Higashiyama
Shigeki
S
Department of Medical Biochemistry, Ehime University School of Medicine.
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism*; D003864:Depression, Chemical; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C107086:KB R7785; D008565:Membrane Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D008666:Metalloendopeptidases; D005998:Glycine