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

Masanori Asakura; Masafumi Kitakaze; Seiji Takashima; Yulin Liao; Fuminobu Ishikura; Tsuyoshi Yoshinaka; Hiroshi Ohmoto; Koichi Node; Kohichiro Yoshino; Hiroshi Ishiguro; Hiroshi Asanuma; Shoji Sanada; Yasushi Matsumura; Hiroshi Takeda; Shintaro Beppu; Michihiko Tada; Masatsugu Hori; Shigeki Higashiyama

doi:10.1038/nm0102-35

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.

Authors

Masanori Asakura¹, Masafumi Kitakaze, Seiji Takashima, Yulin Liao, Fuminobu Ishikura, Tsuyoshi Yoshinaka, Hiroshi Ohmoto, Koichi Node, Kohichiro Yoshino, Hiroshi Ishiguro, Hiroshi Asanuma, Shoji Sanada, Yasushi Matsumura, Hiroshi Takeda, Shintaro Beppu, Michihiko Tada, Masatsugu Hori, Shigeki Higashiyama

Affiliation

¹ Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.

PMID: 11786904
DOI: 10.1038/nm0102-35

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 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

Substances

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