Abstract
Chymase converts angiotensin (Ang) I to Ang II, which may promote the development of liver fibrosis. In this study, a chymase inhibitor TY-51469 attenuated dimethylnitrosamine (DMN)-induced liver fibrosis was examined. A total of 44 rats were randomly divided into three groups: The model group, the control group, and the chymase inhibitor treatment (Chy-I) group. The rats were given intraperitoneal injections of 1% DMN (1 ml/mg). On the first day after the DMN challenge, the rats in the Chy-I group was given chymase inhibitor (10 mg/kg) by gastric lavage daily for 42 days; the other groups were given sterile saline. Liver tissue samples were collected on days 14, 28 and 56. The chymase levels were determined by enzyme-linked immunosorbent assay (ELISA). Collagen type I (Col-I) expression was evaluated by reverse-transcription polymerase chain reaction (RT-PCR). The Col-I in sinusoidal walls were evidently inhibited after the chymase inhibitor treatment, and they were higher in the liver fibrosis model group than in the control group, and significantly lower in the chymase inhibitor group. The chymase levels in the liver were evidently inhibited after the chymase inhibitor treatment, and were higher in the liver fibrosis model group than in the control group. Chymase expression was significantly lower in the Chy-I group. The Col-I mRNA levels were evidently inhibited after the chymase inhibitor treatment, higher in the liver fibrosis model group than in the control group, and significantly lower in the Chy-I group. Chymase inhibitors alleviate DMN-induced liver fibrosis in rats by inhibiting chymase activity and Col-I mRNA expression in liver tissues. Key words: Liver fibrosis, chymase, angiotensin II, collagen type I.
Highlights
Chymase is a cell serum protease present in human vascular tissueS and mastocytes, and it decomposes angiotensin (Ang) 1 into Ang II
The Collagen type I (Col-I) in sinusoidal walls were inhibited after the chymase inhibitor treatment, and they were higher in the liver fibrosis model group than in the control group, and significantly lower in the chymase inhibitor group
Accumulation of chymase-positive cells was observed in fibrotic liver regions in chronic cirrhosis patients, suggesting that chymase-dependent Ang II formation pathways may have a close relationship with the occurrence of liver fibrosis (Shimizu et al, 2003; Komeda et al, 2008)
Summary
Chymase is a cell serum protease present in human vascular tissueS and mastocytes, and it decomposes angiotensin (Ang) 1 into Ang II. Ang II induces vascular smooth muscle contractions and promotes the proliferation, hypertrophy, and migration of smooth muscle cells and fibroblasts (Takai et al, 2009). Liver fibrosis is a necessary stage that develops into all sorts of chronic liver diseases such as cirrhosis and liver cancer. Its key stage is hepatic stellate cell activation, and transforms into myofibroblast-like cells and fibroblasts. Ang II plays an important role in blood pressure regulation, maintains fluid balance, and participates in the pathologic development of liver fibrosis. The local renin–angiotensin system (RAS) promotes hepatic stellate cell activation, and participates in the development of liver fibrosis through the Ang II type 1 receptor (AT1R) (Yoshiji et al, 2002; Mashall et al, 2000). Ang II stimulates the expression of transforming growth factor -β1 (TGF-β1) to promote liver fibrosis
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