Mutant MMP-9 and HGF Gene Transfer Enhance Resolution of CCl4-Induced Liver Fibrosis in Rats: Role of ASH1 and EZH2 Methyltransferases Repression
| Autor: | Elke Roeb, Hatem Allam, Salama R. Abdel Raheim, Mahmoud A. El-Rehany, Ayman Al-Hendy, Olfat Hammam, Hend Abdel-Ghany, Heba Marey, Hussein M. Atta, Maggie M. Ramzy, Martin Roderfeld |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology Cirrhosis Methyltransferase medicine.medical_treatment lcsh:Medicine Liver Cirrhosis Experimental Chronic Liver Disease chemistry.chemical_compound Fibrosis Medicine and Health Sciences lcsh:Science Carbon Tetrachloride Multidisciplinary biology Hepatocyte Growth Factor Reverse Transcriptase Polymerase Chain Reaction Liver Diseases Gene Transfer Techniques Polycomb Repressive Complex 2 Matrix Metalloproteinase 9 Liver Fibrosis Hepatocyte growth factor Research Article medicine.drug medicine.medical_specialty Genetic Vectors Intraperitoneal injection Enzyme-Linked Immunosorbent Assay CCL4 Gastroenterology and Hepatology Collagen Type I Adenoviridae Internal medicine medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Rats Wistar Sirius Red Tissue Inhibitor of Metalloproteinase-1 lcsh:R Muscle Smooth Genetic Therapy Histone-Lysine N-Methyltransferase Methyltransferases Transforming growth factor beta medicine.disease Actins Collagen Type I alpha 1 Chain Endocrinology chemistry Mutation biology.protein lcsh:Q Mutant Proteins |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 11, p e112384 (2014) |
| ISSN: | 1932-6203 |
| Popis: | Hepatocyte growth factor (HGF) gene transfer inhibits liver fibrosis by regulating aberrant cellular functions, while mutant matrix metalloproteinase-9 (mMMP-9) enhances matrix degradation by neutralizing the elevated tissue inhibitor of metalloproteinase-1 (TIMP-1). It was shown that ASH1 and EZH2 methyltransferases are involved in development of liver fibrosis; however, their role in the resolution phase of liver fibrosis has not been investigated. This study evaluated the role of ASH1 and EZH2 in two mechanistically different therapeutic modalities, HGF and mMMP-9 gene transfer in CCl4 induced rat liver fibrosis. Liver fibrosis was induced in rats with twice a week intraperitoneal injection of CCl4 for 8 weeks. Adenovirus vectors encoding mMMP-9 or HGF genes were injected through tail vein at weeks six and seven and were sacrificed one week after the second injection. A healthy animal group was likewise injected with saline to serve as a negative control. Rats treated with mMMP-9 showed significantly lower fibrosis score, less Sirius red stained collagen area, reduced hydroxyproline and ALT concentration, decreased transforming growth factor beta 1 (TGF-β1) mRNA and lower labeling indices of α smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) stained cells compared with HGF- or saline-treated rats. Furthermore, TIMP-1 protein expression in mMMP-9 group was markedly reduced compared with all fibrotic groups. ASH1 and EZH2 protein expression was significantly elevated in fibrotic liver and significantly decreased in mMMP-9- and HGF-treated compared to saline-treated fibrotic livers with further reduction in the mMMP-9 group. Conclusion: Gene transfer of mMMP-9 and HGF reduced liver fibrosis in rats. ASH1 and EZH2 methyltransferases are significantly reduced in mMMP-9 and HGF treated rats which underlines the central role of these enzymes during fibrogenesis. Future studies should evaluate the role of selective pharmacologic inhibitors of ASH1 and EZH2 in resolution of liver fibrosis. |
| Databáze: | OpenAIRE |
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