(4-(n-hydroxyamino)-2r-isobutyl-3s-methylsuccinyl)-l-phenylglycine-n-methylamide and Hypertension

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.

Topics: ADAM Proteins; ADAM12 Protein; Angiotensin II; Animals; Aorta, Thoracic; Cardiomegaly; Disease Models, Animal; Disintegrins; Epidermal Growth Factor; ErbB Receptors; Glycine; GTP-Binding Proteins; Heart Ventricles; Heparin-binding EGF-like Growth Factor; Hydroxamic Acids; Hypertension; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Metalloendopeptidases; Phenylephrine; Protease Inhibitors; Protein Processing, Post-Translational; Rats; Signal Transduction; Systole; Transcriptional Activation