Transcriptional regulation of cardiac fibroblast phenotypic plasticity

Cardiac fibroblasts play critical roles in the maintenance of cardiac structure and the response to cardiac insult. Extracellular matrix deposition by activated resident cardiac fibroblasts, called myofibroblasts, is an essential wound healing response. However, persistent fibroblast activation contributes to pathological fibrosis and cardiac chamber stiffening, which can cause diastolic dysfunction, heart failure, and initiate lethal arrhythmias. The dynamic and phenotypically plastic nature of cardiac fibroblasts is governed in part by the transcriptional regulation of genes encoding extracellular matrix molecules. Understanding how fibroblasts integrate various biomechanical cues into a precise transcriptional response may uncover therapeutic strategies to prevent fibrosis. Here, we provide an overview of the recent literature on transcriptional control of cardiac fibroblast plasticity and fibrosis, with a focus on canonical and noncanonical transforming growth factor beta signaling, biomechanical regulation of Hippo/yes-associated protein and Rho/myocardin-related transcription factor signaling, and metabolic and epigenetic control of fibroblast activation.