HDAC2 inhibitor CAY10683 reduces intestinal epithelial cell apoptosis by inhibiting mitochondrial apoptosis pathway in acute liver failure

Abstract

Introduction: Histone deacetylases (HDAC) inhibitor has the effect of anti-tumor and inhibiting apoptosis, and could inhibit the release of inflammatory factors, reducing the damage to liver and enterocytes in acute liver failure (ALF). HDAC2 specific inhibitor CAY10683 was used to verify the protective effect on acute liver failure through reducing intestinal epithelial cell apoptosis by inhibiting mitochondrial apoptosis pathway.

Materials and methods: Lipopolysaccharide/D-galactosamine (LPS/D-GalN) was used to induce ALF in Sprague-Dawley rats. A total of 18 healthy rats were randomly divided into three groups. Rats in ALF group and CAY10683 group were given the same amount of normal sodium or CAY10683 2 hours before ALF model protocol was conducted. NCM460 cells were given LPS/D-GalN to establish an apoptotic model. Flow cytometry analysis was used to determine the apoptosis of enterocytes, and TUNEL assay was used to observe the apoptosis of NCM460 cells. The expression of bax was observed by immunofluorescence. The expression of histone proteins, HDAC2 and molecules in the apoptotic signaling pathway were determined by Western blotting and real-time PCR.

Results: CAY10683 improves histological and functional changes in ALF model. Compared with control group, LPS/D-GalN induced massive apoptosis of rat intestinal tissues and NCM460 cells (P<0.05), and the apoptosis rate was significantly reduced after CAY10683 treatment (P<0.05). The expression of bax was increased significantly in the model groups (P<0.05), and reduced with the treatment of CAY10683 (P<0.05). Compared with the model group, CAY10683 inhibits mitochondrial apoptosis in intestinal tissues and NCM460 cells (P<0.05).

Conclusion: CAY10683 reduces the damage to liver and intestinal tissue, and plays an important role in inhibiting mitochondrial apoptosis in ALF rats and in NCM460 cells.