The role of fibroblast-specific canonical TGFb signaling in cardiac fibrosis

Heart failure is characterized by cardiomyocyte loss, interstitial fibrosis, and chamber remodeling. During physiological conditions cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure. Injury... [ view full abstract ]

Heart failure is characterized by cardiomyocyte loss, interstitial fibrosis, and chamber remodeling. During physiological conditions cardiac fibroblasts contribute to the homeostatic maintenance of myocardial structure. Injury and/or cytokine stimulation activate fibroblasts which transdifferentiate into myofibroblasts; these secrete extracellular matrix (ECM) for wound healing and tissue remodeling. 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 pathological remodeling of the ventricles. During heart disease, cardiomyocytes, immune cells and fibroblasts secrete the cytokine transforming growth factor-TGF, which activates fibroblasts and promotes their conversion to myofibroblasts. Manipulation of TGF in cardiomyocytes reduced the fibrotic response after pressure overload; however heart failure was not improved because deleterious TGF signaling in fibroblasts persistedHere we utilized a novel myofibroblast-specific inducible Cre-expressing mouse line (Periostin-MerCreMer) to examine canonical (Smad2/3) TGF 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 TGF signaling indicated that TGF initiates myofibroblast transformation and myocardial fibrosis with injury to the heart, but that ultimately other pathways can fully compensate and fibrosis eventually occurs.