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 (Cry AB^R120G), 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 Cry AB^R120G, we have partially ablated TGF -β signaling in cardiac myofibroblasts to observe whether cardiac fibrosis is reduced despite the ongoing pathogenic stimulus of Cry AB^R120G production. Transgenic Cry AB^R120G mice were crossed with mice containing a floxed allele of TGF -β receptor 2 ( Tgfbr2 ^f/f). The double transgenic animals were subsequently crossed to another transgenic line in which Cre expression was driven from the periostin locus ( Postn) so that Tgfbr2 would be ablated with myofibroblast conversion. Structural and functional assays were then used to determine whether general fibrosis was affected and cardiac function rescued in Cry AB^R120G mice lacking Tgfbr2 in the myofibroblasts. Ablation of myofibroblast specific TGF -β signaling led to decreased morbidity in a proteotoxic disease resulting from cardiomyocyte autonomous expression of Cry AB^R120G. Cardiac fibrosis was decreased and hypertrophy was also significantly attenuated, with a significant improvement in survival probability over time, even though the primary proteotoxic insult continued. Conclusions Myofibroblast-targeted knockdown of Tgfbr2 signaling resulted in reduced fibrosis and improved cardiac function, leading to improved probability of survival.