Aims:Neovascularization plays a crucial role in liver fibrosis(LF),and blocking vascular endothelial growth factor receptors(VEGFR)has been shown to improve fibrosis.The aim of our study was to investigate the role of...Aims:Neovascularization plays a crucial role in liver fibrosis(LF),and blocking vascular endothelial growth factor receptors(VEGFR)has been shown to improve fibrosis.The aim of our study was to investigate the role of dual neovascularization targets,VEGFR,and platelet-derived growth factor receptor(PDGFR),in ameliorating fibrosis.Methods:In vitro,we observed the effects of apatinib(APA)(a VEGFR inhibitor)and donafenib(DON)(a VEGFR and PDGFR inhibitor)on the activation,proliferation,and apoptosis of hepatic stellate cells(HSCs)from rats and humans.In vivo,we established a thioacetamide(TAA)-induced liver fibrosis rat model to explore the antifibrosis effect of APA and DON.We used the method of random table to randomly divide the rats into 4 groups.We detected the expression of angiogenesis-related proteins using Western blot and immunohistochemistry.Results:APA and DON inhibited the proliferation and activation of HSCs,promoted apoptosis of HSCs,and arrested the S phase of the cell cycle in vitro.We also found that DON had a stronger inhibitory effect on HSCs.In vivo,APA and DON ameliorated liver fibrosis,reduced collagen deposition andα-SMA expression in rats,and DON had a stronger improvement effect.APA and DON downregulated the expression of VEGFR2 while inhibiting the phosphorylation of Akt and ERK1/2.DON can act through both VEGF and PDGF pathways,whereas APA can only act through the VEGF pathway.Conclusion:Antiangiogenesis is a promising approach for the treatment of fibrosis.Compared with a single-target drug(APA),the dual-target drug(DON)can achieve better therapeutic effects.展开更多
基金National Natural Science Foundation of China,Grant/Award Number:81873917。
文摘Aims:Neovascularization plays a crucial role in liver fibrosis(LF),and blocking vascular endothelial growth factor receptors(VEGFR)has been shown to improve fibrosis.The aim of our study was to investigate the role of dual neovascularization targets,VEGFR,and platelet-derived growth factor receptor(PDGFR),in ameliorating fibrosis.Methods:In vitro,we observed the effects of apatinib(APA)(a VEGFR inhibitor)and donafenib(DON)(a VEGFR and PDGFR inhibitor)on the activation,proliferation,and apoptosis of hepatic stellate cells(HSCs)from rats and humans.In vivo,we established a thioacetamide(TAA)-induced liver fibrosis rat model to explore the antifibrosis effect of APA and DON.We used the method of random table to randomly divide the rats into 4 groups.We detected the expression of angiogenesis-related proteins using Western blot and immunohistochemistry.Results:APA and DON inhibited the proliferation and activation of HSCs,promoted apoptosis of HSCs,and arrested the S phase of the cell cycle in vitro.We also found that DON had a stronger inhibitory effect on HSCs.In vivo,APA and DON ameliorated liver fibrosis,reduced collagen deposition andα-SMA expression in rats,and DON had a stronger improvement effect.APA and DON downregulated the expression of VEGFR2 while inhibiting the phosphorylation of Akt and ERK1/2.DON can act through both VEGF and PDGF pathways,whereas APA can only act through the VEGF pathway.Conclusion:Antiangiogenesis is a promising approach for the treatment of fibrosis.Compared with a single-target drug(APA),the dual-target drug(DON)can achieve better therapeutic effects.
