title: Characterization of fibrosis-promoting factors and siRNA-mediated therapies in C-protein-induced experimental autoimmune myocarditis.
abstract: Due to poor proliferation abilities of cardiomyocytes, the repair process in the heart after insults is often associated with fibrosis formation. In this study, we characterized inflammation and/or fibrosis-related molecules in the heart with experimental autoimmune carditis. Immunohistochemical examinations reveled that expression of tenascin-C (TNC), matrix metalloproteinase-9 (MMP-9), transforming growth factorβ1 (TGF-β1), connective tissue growth factor (CTGF) and α smooth muscle cell actin (αSMA) peaked at 2 weeks post-immunization but only TGF-β1 expression was sustained at 8 weeks. Administration of siRNAs for MMP-2 (siMMP-2) and for MMP-9 (siMMP-9) alone did not modulate inflammation and fibrosis. In contrast, simultaneous administration of siMMP-2 and siMMP-9 significantly reduced inflammation and fibrosis. Of note, siRNA treatment for TGF-β1, which is an anti-inflammatory cytokine, increased inflammation and decreased fibrosis. These findings suggest that in case of diseases characterized by initial inflammation and subsequent fibrosis, immunotherapies should target inflammation, not fibrosis, because the latter therapies exacerbate inflammation.
authors.affiliation: Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan. matsumoto-yo@igakuken.or.jp
authors.forename: Yoh
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Niimi
authors.forename: Kuniko
authors.initials: K
authors.lastname: Kohyama
mesh_terms: D000199:Actins / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000276:immunology; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009130:Muscle, Smooth / Q000737:chemistry; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D034622:RNA Interference / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D019063:Tenascin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000099163:Myosin Binding Protein C
chemical_list: D000199:Actins; D002352:Carrier Proteins; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010446:Peptide Fragments; D019063:Tenascin; D053773:Transforming Growth Factor beta1; D000099163:Myosin Binding Protein C; C526316:CCN2 protein, rat