Cardiac Fibrosis in Proteotoxic Cardiac Disease is Dependent Upon Myofibroblast TGF‐β Signaling

Background Transforming growth factor beta (TGF‐β) is an important cytokine in mediating the cardiac fibrosis that often accompanies pathogenic cardiac remodeling. Cardiomyocyte‐specific expression of a mutant αB‐crystallin (CryABR120G), which causes human desmin‐related cardiomyopathy, results in significant cardiac fibrosis. During onset of fibrosis, fibroblasts are activated to the so‐called myofibroblast state and TGF‐β binding mediates an essential signaling pathway underlying this process. Here, we test the hypothesis that fibroblast‐based TGF‐β signaling can result in significant cardiac fibrosis in a disease model of cardiac proteotoxicity that has an exclusive cardiomyocyte‐based etiology. Methods and Results Against the background of cardiomyocyte‐restricted expression of CryABR120G, we have partially ablated TGF‐β signaling in cardiac myofibroblasts to observe whether cardiac fibrosis is reduced despite the ongoing pathogenic stimulus of CryABR120G production. Transgenic CryABR120G mice were cr...