Transcriptional Control of Fibroblast Plasticity

Heart disease is associated with the accumulation of resident cardiac fibroblasts that secrete extracellular matrix (ECM) and drive the development of pathological fibrosis and heart failure. However, the mechanisms underlying fibroblast proliferation and activation remain poorly defined. To address this gap in understanding we have utilized transcriptional profiling to characterize the cardiac fibroblast phenotype in health and disease. Cardiac fibroblasts exhibit dynamic changes in genes encoding cell cycle regulators and ECM proteins. Here, we report that the cardiac fibroblast cell cycle is in part controlled by Sprr2b, a small proline‐rich protein that is induced in heart disease and extinguished during exercise. Sprr2b is a novel regulatory component of the USP7/MDM2‐containing ubiquitination complex. Sprr2b stimulates MDM2‐dependent p53 degradation, thus facilitating the proliferation of pathological cardiac fibroblasts. These findings establish a paradigm of transcriptional regulation that governs cardiac fibroblast phenotypic plasticity and the development of pathological cardiac fibrosis. Support or Funding Information NIH / NHLBI R01‐HL133761 and R01‐HL120919 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .