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
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
DOI: 10.1371/journal.pone.0112384
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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