Premium
Mechanoregulated expression of smooth muscle alpha‐actin in myofibroblasts is mediated by MRTF‐A localization and actin dynamics
Author(s) -
Tomasek James J,
Haaksma Carol J,
McRae Joel K,
Risinger George M,
Howard Eric W
Publication year - 2008
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.22.1_supplement.521.7
Subject(s) - myofibroblast , microbiology and biotechnology , myocardin , actin , cytoplasm , chemistry , gene knockdown , cytochalasin d , serum response factor , transcription factor , cytoskeleton , biochemistry , biology , cell , pathology , medicine , gene , fibrosis
Expression of smooth muscle α‐actin (SMAA), which promotes myofibroblast contractile function and wound closure, is mechanoregulated. We hypothesize that mechanoregulated actin dynamics control the localization of myocardin related transcription factor‐A (MRTF‐A) thereby mechanoregulating SMAA expression. G‐actin has been shown to bind MRTF‐A, thus sequestering the MRTF‐A in the cytoplasm and blocking MRTF‐A activated SMAA expression. MRTF‐A is necessary for SMAA expression as demonstrated by shRNA knockdown. Decreasing myofibroblast tension with blebbistatin, or culturing myofibroblasts on a compliant collagen matrix, resulted in a loss of stress fibers, a higher G‐/F‐actin ratio, MRTF‐A localization to the cytoplasm, and decreased SMAA promoter activity. Treating cells on a compliant matrix with jasplakinolide or cytochalasin D resulted in increased F‐actin, MRTF‐A localization to the nucleus and increased SMAA promoter activity. Together, these results provide a model for mechanoregulated SMAA expression; in response to a stiff substratum G‐actin is assembled into F‐actin resulting in the release of MRTF‐A, expression of SMAA, and myofibroblast differentiation. Funded by NIH grant R01 GM60651