Myocardin‐ related transcription factor A regulates myofibroblast formation and function

Abstract

Myofibroblasts (MFs) differentiate from fibroblasts and function to facilitate wound closure. Under pathological conditions, MFs fail to undergo apoptosis and continue to remodel the extracellular matrix, leading to increased contracture of connective tissue. MFs are characterized as having "super‐mature" focal adhesions and expression of smooth muscle α‐actin (SMAA). Myocardin‐related transcription factors A and B (MRTF‐A/MAL/MKL‐1 and MRTF‐B/MKL‐2) are putative mechanical stress‐induced co‐activators that activate expression of contractile proteins such as SMAA. Small interfering RNA (siRNA) has been used to study the effects of MRTF‐A and MRTF‐B reduction on the MF contractile phenotype in rat embryonic fibroblasts. Decreased SMAA levels, as determined by immunoblot analyses, and reduced contractile force generation, as determined by a wrinkling assay, were observed in cells transfected with MRTF‐A and ‐B‐targeted siRNA. Immunocytochemistry has shown a decrease in the size and number of focal adhesions in these cells when compared to control cells. Finally, transiently transfected myocardin, which acts similarly to constitutively‐active MRTF‐A, increased SMAA promoter activity and increased the contractile ability of cells plated on a deformable wrinkling substrate. These results suggest MRTFs play a critical role in regulating MF formation and function. (Funded by NIH 2R01GM60651)Grant Funding SourceNIH