Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats.
Advanced hepatic fibrosis is characterized by excessive extracellular matrix deposition, where collagen and proteoglycans are the main constituents of scar tissue. In previous studies, we showed that heparanase, a heparan sulfate-degrading enzyme, and vascular endothelial growth factor (VEGF) play an important role during liver development and remodeling. In this communication, we investigated the relationship between heparanase and VEGF in thioacetamide-induced liver fibrosis in rats. Our study shows that heparanase mRNA expression levels correlate with those of VEGF during the induction and recovery stages of liver fibrosis. We further demonstrated that treating fibrotic rat livers with halofuginone (HF), a multipotent antifibrogenic drug, and subsequently subjecting them to hydrodynamics-based transfection with human VEGF-165 resulted in elevated expression of heparanase mRNA. Moreover, these rats demonstrated an improved capacity to regenerate following 70% partial hepatectomy. In vitro, HF stimulated heparanase and VEGF mRNA expression in hepatic stellate cells. Taken together, our results suggest that in addition to the known multiple functions of HF, it also enhances heparanase and VEGF expression and promotes liver regeneration. Accordingly, HF seems to possess ideal properties required to become an excellent antifibrogenic agent in humans.
Ohayon
Olga
O
Department of Anatomy and Cell Biology, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Mawasi
Nidal
N
Pevzner
Anna
A
Tryvitz
Ana
A
Gildor
Tsvia
T
Pines
Mark
M
Rojkind
Marcos
M
Paizi
Melia
M
Spira
Gadi
G
D000818:Animals; D005966:Glucuronidase / Q000378:metabolism*; D006909:Hydroxyproline / Q000032:analysis; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide; D014162:Transfection; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099175:Heparanase
D005966:Glucuronidase; D006909:Hydroxyproline; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D052999:Quinazolinones; D012333:RNA, Messenger; D013853:Thioacetamide; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C010176:halofuginone