Abstract 275: The Role of Fibroblast-specific Canonical TGFβ Signaling in Cardiac Fibrosis

Abstract

Heart failure is a progressive disease characterized by cardiomyocyte loss, interstitial fibrosis, and chamber remodeling. During physiological conditions cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure as well as the maintenance of biochemical and electrical properties of the heart. Injury and/or cytokine stimulation activate fibroblasts which transdifferentiate into myofibroblasts. These newly formed cells secrete extracellular matrix (ECM) for wound healing and tissue remodeling through their contractile activity. Fibrosis mediated by these cells can initially be a beneficial response that acutely scarifies areas after an infarct to prevent wall rupture. However, during chronic disease states such as heart failure, persistent recruitment and activation of fibroblasts leads to excessive deposition of ECM that results in stiffening and pathological remodeling of the ventricles. During chronic heart disease, cardiomyocytes, immune cells and fibroblasts secrete the cytokine transforming growth factor-TGFβ, which activates fibroblasts and promotes their conversion to myofibroblasts. Previous work from Kass lab showed that manipulation of TGFβ by deletion of Tgfbr 1 (type I TGFβ receptor) in cardiomyocytes reduced the fibrotic response after pressure overload. However heart failure was not improved because deleterious TGFβ signaling in fibroblasts persisted. Here we utilized a novel myofibroblast-specific inducible Cre-expressing mouse line (Periostin-MerCreMer) to examine canonical (Smad2/3) TGFβ signaling to determine how these cells and their activation mediate disease in heart failure. Our data indicate that myofibroblast-specific deletion of Smad3 but not Smad2 was sufficient to significantly inhibit myocardial fibrosis after pressure overload, but not ultimately prevent it. Also, myofibroblast specific Smad2/3 double nulls and Tgfbr1/2 double nulls were generated and analyzed. Data from all these myofibroblast-specific mouse models with inhibited TGFβ signaling indicated that TGFβ initiates myofibroblast transformation and myocardial fibrosis with injury to the heart, but that ultimately other pathways can fully compensate and fibrosis eventually occurs.