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 ABR120G), 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 ABR120G, we have partially ablated TGF -β signaling in cardiac myofibroblasts to observe whether cardiac
fibrosis is reduced despite the ongoing pathogenic stimulus of Cry ABR120G production. Transgenic Cry ABR120G 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 ABR120G 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 ABR120G. 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.