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
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
复制标题
DOI：
10.1124/jpet.102.045179
复制
发表时间：
2003-04-01
影响因子：
3.5
通讯作者：
Miyazaki, M
中科院分区：
文献类型：
--
作者：
Takai, S;Jin, D;Miyazaki, M
以前，我们报道了心肌病仓鼠心脏组织中糜酶活性及其mRNA水平随着心脏纤维化的进展而沿着显著增加，但糜酶在纤维化进展中的参与尚不清楚。在培养的人成纤维细胞中，注射人糜酶后，培养基上清液中转化生长因子-β的浓度显著增加。此外，人糜酶剂量依赖性地增加细胞增殖，并且这种糜酶依赖性增殖被糜酶抑制剂Suc-Val-Pro-Phe（p）（OPh）（2）（10 μ M）或抗转化生长因子β抗体（100 μ g/ml）完全抑制。在这项研究中，我们分别使用Bio14.6和F1 B仓鼠作为心肌病和对照仓鼠。心肌病仓鼠从5- 45周龄经口给予新型糜酶抑制剂4-[1-{[双-（4-甲基苯基）甲基]-氨基甲酰基}-3-（2-乙氧基-苄基）-4-氧代-氮杂环丁烷-2-基氧基]-苯甲酸（BCEAB; 100 mg/kg/天）或安慰剂。在安慰剂治疗组中，与对照仓鼠相比，45周龄心肌病仓鼠的心脏糜酶活性显著增加。BCEAB显著降低心肌糜酶活性。心功能指标（+ dP/dt和-dP/dt）经BCEAB治疗后明显改善。通过BCEAB处理，安慰剂处理的仓鼠中I型胶原和III型胶原的mRNA水平分别显著降低至69.6%和76.5%。与安慰剂处理的仓鼠相比，BCEAB处理的仓鼠心脏组织中的纤维化面积被显著抑制至50.7%。因此，糜酶激活转化生长因子β可能在心肌病心脏纤维化和心功能障碍的进展中起重要作用。
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 muM) or an anti-transforming growth factor-beta antibody (100 mug/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.