Carvedilol alleviates the biliary cirrhosis through inhibiting the endoplasmic reticulum stress

P. Gao, B. Yang, H.-Y. Yu, R.-R. Meng, J.-Y. Si

Department of Vascular Surgery, No. 1 People’s Hospital of Jining City, Shandong Province, China. sitou483073@163.com

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• Pharmacology

OBJECTIVE: To investigate the effects of carvedilol on inflammation, apoptosis, and hepatic fibrosis caused by biliary cirrhosis and its mechanisms in mice.

MATERIALS AND METHODS: 60 male C57/BL6 mice were randomly divided into sham-operation group (Sham group, n=20), biliary cirrhosis group (BDL group, n=20) and carvedilol group (CAR group, n=20). The CAR group was treated with gavage using 12.5 mg/kg carvedilol, once a day for 14 consecutive days, while the Sham group and BDL group were treated with gavage using the equivalent normal saline. After that, the mice in Sham group received the laparotomy under chloral hydrate anesthesia, followed by direct abdominal closure. The mice in BDL group and CAR group received the common bile duct ligation after anesthesia for modeling. After modeling, the survival rate of mice in each group was detected, and the blood and liver tissues were taken for detection. The morphological changes in liver tissues and apoptosis in mice in each group were detected and compared. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), superoxide dismutase (SOD), malondialdehyde (MDA), hydroxyproline, and α-smooth muscle actin (α-SMA) were also detected. The mRNA expression levels of pro-inflammatory factors, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), transforming growth factor β-1 (TGF-β1), α-SMA and collagen-1 were detected via reverse transcription-polymerase chain reaction (RT-PCR). The protein expression levels of CHOP (CCAAT-enhancer-binding protein homologous protein), activating transcription factor 4 (ATF4), ATF6, inositol-requiring enzyme 1 (IRE1), phosphorylated Jun N-terminal kinase (pJNK), α-SMA, and collagen-1, were detected via Western-blotting.

RESULTS: Our study showed that carvedilol could significantly alleviate the biliary cirrhosis in mice, and improve the survival rate of mice. The ALT, AST and TBIL levels, severity of cirrhosis, and number of apoptotic cells in CAR group were significantly lower than those in BDL group. The levels of α-SMA and hydroxyproline in CAR group were also significantly lower than those in BDL group. The activity of SOD in CAR group was significantly higher than that in BDL group; the above differences were statistically significant (p<0.05). In addition, it was also found that carvedilol could down-regulate the mRNA expression levels of iNOS, COX-2 and TGF-β1, down-regulate the mRNA and protein expression levels of α-SMA and collagen-1, and negatively regulate the ATF4-CHOP, ATF6-CHOP and IRE1-pJNK signaling pathways.

CONCLUSIONS: Carvedilol has a significant effect on alleviating the biliary cirrhosis in mice, and its relevant mechanism may be that carvedilol inhibits the endoplasmic reticulum stress through the negative regulation of ATF4-CHOP, ATF6-CHOP and IRE1-pJNK signaling pathways, which needs to be confirmed by further in vitro experiments.

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