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Mechanoregulated expression of smooth muscle alpha‐actin in myofibroblasts is mediated by actin dynamics and myocardin related transcription factor‐A localization
Author(s) -
Broiles JoSette LB,
Hinz Boris,
Wipff PierreJean,
Howard Eric W,
Haaksma Carol J,
Tomasek James J
Publication year - 2009
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.23.1_supplement.469.10
Subject(s) - myocardin , microbiology and biotechnology , actin , myofibroblast , transcription factor , serum response factor , chemistry , cytochalasin d , biology , cytoskeleton , biochemistry , cell , pathology , fibrosis , medicine , gene
Myofibroblasts are specialized fibroblasts that facilitate wound closure through expression of smooth muscle (SM) contractile proteins and generation of contractile force on the surrounding matrix. We hypothesize mechanoregulation of SM α‐actin (SMAA) expression in myofibroblasts is mediated by actin dynamics regulating localization of myocardin related transcription factor‐A (MRTF‐A); on compliant substrata, high levels of G‐actin will sequester MRTF‐A, while on stiff substrata decreased G‐actin levels will release MRTF‐A to interact with the SMAA promoter. Rat embryonic fibroblasts cultured on novel deformable substrata of varying stiffness were analyzed. Increasing substratum stiffness resulted in a graded increase in SMAA promoter activity and endogenous mRNA expression, focal adhesion and stress fiber assembly, and MRTF‐A nuclear localization, suggesting that the lack of a critical stiffness acts as a switch. The actin polymerizing agents, jasplakinolide and cytochalasin D, promoted nuclear localization of MRTF‐A and increased SMAA expression, independent of substratum stiffness. Similarly, a constitutively nuclear MRTF‐A promoted SMAA expression independent of substratum stiffness. This work demonstrates that actin dynamics, in response to the mechanical environment, regulate nuclear localization of MRTF‐A and thereby expression of SMAA. Funded by NIH grant R01 GM60651. Grant Funding Source NIH grant R01 GM60651