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Interaction of scleraxis and Smad‐dependent cardiac collagen expression
Author(s) -
Bagchi Rushita A,
Dixon Ian MC,
Czubryt Michael P
Publication year - 2011
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.25.1_supplement.1032.5
Subject(s) - transactivation , smad , cardiac fibrosis , transforming growth factor , chemistry , microbiology and biotechnology , transcription factor , biology , fibrosis , medicine , biochemistry , gene
Deposition of type I collagen is a hallmark of cardiac fibrosis. We have shown that the transcription factor scleraxis ( Scx ) is expressed in cardiac fibroblasts and is sufficient to regulate human collagen Iα2 ( COLIα2 ) expression. Our objective was to study Scx interaction with the fibrotic Smad signalling pathway. We identified specific E box sites within the COLIα2 proximal promoter mediating transactivation by Scx . TGF‐β 1 augmented transactivation of the promoter by Scx , suggesting an additive effect of Scx with TGF‐β 1 signalling pathways. Inhibitory Smad7 partially blunted Scx ‐mediated COLIα2 promoter activation. Receptor Smad3 up‐regulated whereas Smad7 down‐regulated Scx expression in primary rat cardiac fibroblasts, suggesting cross‐talk between Scx and Smad‐mediated COLIα2 expression mechanisms. A dominant‐negative Scx mutant abrogated COLIα2 promoter transactivation by TGF‐β 1 , suggesting that interference with Scx function is sufficient to block pro‐fibrotic signalling. We noted elevated Scx expression in the pressure‐overloaded murine heart following thoracic aortic banding concomitant with increased type I collagen expression. These results support our hypothesis that Scx regulates collagen synthesis and hence may be an important novel target for developing anti‐fibrotic therapies. Supported by Canadian Institutes of Health Research & St. Boniface Hospital Research Foundation.