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Abstract
Protease-activated receptor 2 (PAR-2) plays an important role in the pathogenesis of liver fibrosis. We studied the effect of N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine (ENMD-1068), a PAR-2 antagonist, on the development of CCl4-induced liver fibrosis in mice and activation of hepatic stellate cells (HSCs) isolated from the mice. Before CCl4 injection, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 μL of the vehicle control twice per week for 4 weeks. The isolated HSCs were stimulated by TGF-β1 with or without ENMD-1068 to evaluate the role of PAR-2 in TGF-β1 induced HSCs activation and collagen production. We showed that the levels of ALT/AST, collagen content, and α-smooth muscle actin (α-SMA) were significantly reduced by treatment with ENMD-1068 in CCl4-induced fibrotic mice. Interestingly, we found TGF-β1 signaling-related expression levels of α-SMA, type I and III collagen, and C-terminal phosphorylation of Smad2/3 were significantly decreased in the ENMD-1068 treated HSCs. Moreover, we showed ENMD-1068 treatment inhibited trypsin or SLIGRL-NH2 stimulated calcium release and TGF-β1 induced Smad transcriptional activity in HSCs. We demonstrated that ENMD-1068 reduces HSCs activation and collagen expression through the inhibiton of TGF-β1/Smad signal transduction.
Highlights
Protease-activated receptor 2 (PAR-2) plays an important role in the pathogenesis of liver fibrosis
Despite the relatively large population of patients suffering from hepatic fibrosis and cirrhosis, no efficient and well-tolerated drugs are available for the treatment of this disorder[14]
Increasing evidence suggests that protease-activated receptors (PARs)-2 plays an important role in hepatic stellate cells (HSCs) activation and liver fibrosis, and PAR-2 antagonists may represent a novel therapeutic approach in preventing fibrosis in patients with chronic liver disease[4, 7,8,9, 15]
Summary
Protease-activated receptor 2 (PAR-2) plays an important role in the pathogenesis of liver fibrosis. We studied the effect of N1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine (ENMD-1068), a PAR-2 antagonist, on the development of CCl4-induced liver fibrosis in mice and activation of hepatic stellate cells (HSCs) isolated from the mice. The isolated HSCs were stimulated by TGF-β1 with or without ENMD-1068 to evaluate the role of PAR-2 in TGF-β1 induced HSCs activation and collagen production. Increased PAR-2 expression has been detected as rat stellate cells transformed to a myofibroblastic phenotype, and PAR-2 agonist tryptase and the peptide SLIGRL induced HSCs proliferation and collagen secretion[7]. In line with this finding, the prototypical PAR-2 agonist SLIGKV stimulates the proliferation of human HSCs and TGF-β1 production in a PAR-2 dependent manner[8]. HSCs isolated from mice livers were used to analyze the effect of ENMD-1068 treatment in the activation and collagen release of HSCs
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