Myofibroblast-Specific Tgf Beta Receptor Ii Signaling In The Fibrotic Response To Cardiac Myosin Binding Protein C-Induced Cardiomyopathy

Rationale: Hypertrophic cardiomyopathy occurs with a frequency of about 1 in 500 people. Approximately 30% of those affected carry mutations within the gene encoding cMyBP-C (cardiac myosin binding protein C). Cardiac stress, as well as cMyBP-C mutations, can trigger production of a 40kDa truncated fragment derived from the amino terminus of cMyBP-C (Mybpc3(40kDa)). Expression of the 40kDa fragment in mouse cardiomyocytes leads to hypertrophy, fibrosis, and heart failure. Here we use genetic approaches to establish a causal role for excessive myofibroblast activation in a slow, progressive genetic cardiomyopathy-one that is driven by a cardiomyocyteintrinsic genetic perturbation that models an important human disease.Objective: TGF beta (transforming growth factor-beta) signaling is implicated in a variety of fibrotic processes, and the goal of this study was to define the role of myofibroblast TGF beta signaling during chronic Mybpc3(40kDa) expression.Methods and Results: To specifically block TGF beta signaling only in the activated myofibroblasts in Mybpc34(0kDa) transgenic mice and quadruple compound mutant mice were generated, in which the TGF beta receptor II (T beta RII) alleles (Tgfbr2) were ablated using the periostin (Postn) allele, myofibroblast-specific, tamoxifen-inducible Cre (Postnmcm) gene-targeted line. Tgfbr2 was ablated either early or late during pathological fibrosis. Early myofibroblast-specific Tgfbr2 ablation during the fibrotic response reduced cardiac fibrosis, alleviated cardiac hypertrophy, preserved cardiac function, and increased lifespan of the Mybpc3(40kDa) transgenic mice. Tgfbr2 ablation late in the pathological process reduced cardiac fibrosis, preserved cardiac function, and prolonged Mybpc3(40kDa) mouse survival but failed to reverse cardiac hypertrophy.Conclusions: Fibrosis and cardiac dysfunction induced by cardiomyocyte-specific expression of Mybpc3(40kDa) were significantly decreased by Tgfbr2 ablation in the myofibroblast. Surprisingly, preexisting fibrosis was partially reversed if the gene was ablated subsequent to fibrotic deposition, suggesting that continued TGF beta signaling through the myofibroblasts was needed to maintain the heart fibrotic response to a chronic, disease-causing cardiomyocyte-only stimulus.