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Identification of novel scleraxis gene targets in cardiac myofibroblasts
Author(s) -
Bagchi Rushita,
Roche Patricia,
Schweitzer Ronen,
Czubryt Michael
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1129.13
Subject(s) - decorin , versican , myofibroblast , microbiology and biotechnology , cardiac fibrosis , gene expression , extracellular matrix , biology , fibrosis , cancer research , proteoglycan , pathology , gene , medicine , genetics
Cardiac fibrosis is a significant clinical problem yet lacks effective therapies. We have shown that the transcription factor scleraxis is a key regulator of collagen 1α2 gene expression in cardiac myofibroblasts. We now identify novel scleraxis gene targets via gain‐/loss‐of‐function. Scleraxis over‐expression in primary cardiac myofibroblasts decreased the expression of matrix remodeling enzymes matrix metalloproteinases 9 and 11 and tissue inhibitor of metalloproteinases 3. Expression of the proteoglycans versican and decorin were decreased following scleraxis overexpression, yet we observed no change in decorin and a loss of versican in scleraxis null hearts. The expression of thrombospondin 4 and the myofibroblast marker α‐smooth muscle actin (αSMA) was increased by scleraxis overexpression and strongly down‐regulated in scleraxis null hearts, and may thus represent direct scleraxis gene targets. Our results show that scleraxis exerts wide‐ranging effects on extracellular matrix‐related gene expression, with the effect on αSMA expression suggesting that scleraxis may contribute to the fibroblast‐to‐myofibroblast transition that accompanies cardiac fibrosis, further supporting our general hypothesis that scleraxis represents a novel therapeutic target for this disease. Supported by the Canadian Institutes of Health Research & the St. Boniface Hospital Research Foundation.