A novel chymase inhibitor, 4-[1-([bis-(4-methyl-phenyl)-methyl]-carbamoyl)3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB), suppressed cardiac fibrosis in cardiomyopathic hamsters.

Abstract

Previously, we reported that levels of chymase activity and its mRNA in cardiac tissues were significantly increased along with progression of cardiac fibrosis in cardiomyopathic hamsters, but the involvement of chymase in the progression of fibrosis has been unclear. In cultured human fibroblasts, the concentration of transforming growth factor-beta in the supernatant of medium was significantly increased after injection of human chymase. Furthermore, human chymase dose dependently increased cell proliferation, and this chymase-dependent proliferation was completely suppressed by a chymase inhibitor, Suc-Val-Pro-Phe(p)(OPh)(2) (10 micro M) or an anti-transforming growth factor-beta antibody (100 micro g/ml). In this study, we used Bio14.6 and F1B hamsters as cardiomyopathic and control hamsters, respectively. Cardiomyopathic hamsters were orally administered a novel chymase inhibitor, 4-[1-([bis-(4-methylphenyl)-methyl]-carbamoyl)-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB; 100 mg/kg per day), or placebo from 5- to 45-week-old. In the placebo-treated group, the cardiac chymase activity in cardiomyopathic hamsters 45 weeks old was significantly increased compared with that in control hamsters. BCEAB significantly reduced the cardiac chymase activity. The indexes (+dP/dt and -dP/dt) of cardiac function were significantly improved by treatment with BCEAB. The mRNA levels of collagen I and collagen III in the placebo-treated hamsters were significantly reduced to 69.6 and 76.5% by treatment with BCEAB, respectively. The fibrotic area in cardiac tissues in the BCEAB-treated hamsters was significantly suppressed to 50.7% compared with that in the placebo-treated treated hamsters. Therefore, the activation of transforming growth factor-beta by chymase may play an important role in the progression of cardiac fibrosis and cardiac dysfunction in cardiomyopathy.

• Authors: Shinji Takai, Denan Jin, Masato Sakaguchi, Satoru Katayama, Michiko Muramatsu, Minoru Sakaguchi, Eiko Matsumura, Shokei Kim, Mizuo Miyazaki
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 305 Issue 1 Pg. 17-23 (Apr 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12649348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(1-((bis(4-methylphenyl)methyl)carbamoyl)-3-(2-ethoxybenzyl)-4-oxoazetidine-2-yloxy)benzoic acid
• Azetidines
• Benzoates
• Enzyme Inhibitors
• Serine Endopeptidases
• Chymases

Topics

• Animals
• Azetidines (therapeutic use)
• Benzoates (therapeutic use)
• Cardiomyopathies (complications)
• Cells, Cultured
• Chymases
• Cricetinae
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Fibrosis (etiology, prevention & control)
• Humans
• Male
• Serine Endopeptidases (metabolism)