Fibrotic remodeling of the heart in response to injury contributes to heart failure, yet therapies to treat fibrosis remain elusive. Yes-associated protein (YAP) is activated in cardiac fibroblasts by myocardial infarction, and genetic inhibition of fibroblast YAP attenuates myocardial infarction-induced cardiac dysfunction and fibrosis. YAP promotes myofibroblast differentiation and associated extracellular matrix gene expression through engagement of TEA domain transcription factor 1 and subsequent de novo expression of myocardin-related transcription factor A. Thus, fibroblast YAP is a promising therapeutic target to prevent fibrotic remodeling and heart failure.

Megakaryoblastic leukemia 1 (MKL1) is a member of the MKL family of serum response factor (SRF) coactivators. Here we have identified three rat MKL1 transcripts: two are homologues of mouse MKL1 transcripts, full-length MKL1 (FLMKL1) and basic, SAP, and coiled-coil domains (BSAC), the third is a novel transcript, MKL1-elongated derivative of yield (MELODY). These rat MKL1 transcripts are differentially expressed in a wide variety of tissues with highest levels in testis and brain. During brain development, these transcripts display differential patterns of expression. The FLMKL1 transcript encodes two isoforms that utilize distinct translation start sites. The longer form possesses three actin-binding RPXXXEL (RPEL) motifs and the shorter form, MKL1met only has two RPEL motifs. All four rat MKL1 isoforms, FLMKL1, BSAC, MKL1met and MELODY increased SRF-mediated transcription, but not CREB-mediated transcription. Accordingly, the differential expression of MKL1 isoforms may help fine-tune gene expression during brain development.