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

Nat Med. 2002 Jan;8(1):35-40. doi: 10.1038/nm0102-35.


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 types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins
  • ADAM12 Protein
  • Angiotensin II / pharmacology
  • Animals
  • Aorta, Thoracic / surgery
  • Cardiomegaly / drug therapy*
  • Disease Models, Animal
  • Disintegrins / antagonists & inhibitors*
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / genetics
  • GTP-Binding Proteins / metabolism
  • Glycine / analogs & derivatives*
  • Glycine / therapeutic use*
  • Heart Ventricles
  • Heparin-binding EGF-like Growth Factor
  • Hydroxamic Acids / therapeutic use*
  • Hypertension
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Membrane Proteins / antagonists & inhibitors*
  • Metalloendopeptidases / antagonists & inhibitors*
  • Phenylephrine / pharmacology
  • Protease Inhibitors / therapeutic use*
  • Protein Processing, Post-Translational / drug effects
  • Rats
  • Signal Transduction
  • Systole
  • Transcriptional Activation


  • Disintegrins
  • Hbegf protein, mouse
  • Hbegf protein, rat
  • Heparin-binding EGF-like Growth Factor
  • Hydroxamic Acids
  • Intercellular Signaling Peptides and Proteins
  • KB R7785
  • Membrane Proteins
  • Protease Inhibitors
  • Angiotensin II
  • Phenylephrine
  • Epidermal Growth Factor
  • ErbB Receptors
  • ADAM Proteins
  • ADAM12 Protein
  • Metalloendopeptidases
  • GTP-Binding Proteins
  • Glycine