Abstract 262: Myofibroblast-Specific Transforming Growth Factor β Suppression Reduces Fibrosis in a Proteotoxic CryabR120g Mouse Model of Heart Failure

Introduction: Transforming Growth Factor beta (TGFβ) is an important cytokine in mediating cardiac fibrosis. Cardiomyocyte-specific expression of a mutant αB-crystallin (CryAB R120G ) that is responsible for human Desmin Related Myopathy results in significant cardiac fibrosis and cardiac remodeling leading to heart failure. Onset of fibrosis is initiated by the activation of a quiescent fibroblast population to an active, “myofibroblast” state and TGFβ binding is thought to mediate an essential signaling pathway underlying this process. Our central hypothesis is that myofibroblast-based TGFβ signaling can result in significant cardiac fibrosis. Here, we have partially ablated TGFβ signaling in cardiac myofibroblasts to observe if cardiac fibrosis is altered. Objective: To understand the contributions of myofibroblast-based TGFβ signaling to the development of cardiac fibrosis. Methods and Results: To test the hypothesis we partially ablated myofibroblast specific TGFβ signaling by crossing CryAB R120G mice with mice containing a floxed allele of TGFβ’s receptor 1 (TGFβr1). The double transgenic animals were further crossed with activated myofibroblast specific Cre mice in which Cre expression was driven off the periostin promoter so that TGFβr1 would be ablated subsequent to myofibroblast conversion as the periostin promoter became active. Echocardiography, Masson’s Trichome staining, the hydroxyproline assay, PCR arrays, immunohistochemistry and western blots were used to characterize fibrosis and cardiac function in mice lacking TGFβr1 in the myofibroblasts were used to characterize the resultant animals. Conclusion: Myofibroblast-targeted knockdown of Tgfβr1 signaling resulted in reduced fibrosis and improved cardiac function.