Abstract 11654: Myofibroblast Smad1 Activation Restrains Cardiac Fibrosis and Attenuates Post-Myocardial Infarction Adverse Remodeling

Abstract

Cardiac fibroblasts play a pivotal role in repair and remodeling of myocardial infarction (MI) by transforming to myofibroblasts, and acquiring inflammatory, proangiogenic, or matrix-synthetic phenotypes. Members of the Transforming Growth Factor (TGF)β superfamily (including TGFβs and BMPs) are activated following MI and play an important role in regulating fibroblast phenotype, and cardiac fibrosis. Canonical TGFβ superfamily signaling is mediated through the receptor-activated Smads: TGF-βs activate Smad2/3, whereas BMPs predominantly stimulate the Smad1/5 cascade. Smad3 signaling plays an important role in activation of infarct myofibroblasts; however, the role of the Smad1 pathway has not been studied. We hypothesized that fibroblast-specific actions of Smad1 regulate repair and remodeling in the infarcted myocardium. In mouse infarcts, Smad1 was activated in infiltrating myofibroblasts 7 days after coronary occlusion, not only by BMPs but also by TGF-β isoforms. In order to examine the effects of Smad1 in infarct fibroblasts, we generated mice with myofibroblast-specific Smad1 loss (MFS1KO). Echocardiography at 7 and 28 days following MI revealed that MFS1KO mice had accentuated systolic dysfunction, and increased left ventricular dilation (p<0.01, N=13-49) . Worse adverse remodeling in infarcted MFS1KO hearts was associated with scar expansion, and accentuated fibrosis. Smad1 knockdown in control or TGF-β1-stimulated cardiac fibroblasts increased mRNA levels of structural and matricellular genes (including Col1a1, Col3a1, Postn, Thbs1&3 ) while reducing matrix metalloproteinase levels. Analysis of unbiased RNA-seq data revealed that Smad1 loss activates pathways involved in matrix regulation, and collagen biosynthesis, and that the anti-fibrotic actions of Smad1 are carried out through inhibition of pro-fibrotic cascades as the TGF-β/Smad3 axis, p53, and IL4/STAT6 signaling. In conclusion, Smad1 activation in infarct myofibroblasts restrains the fibrotic response and protects the infarcted heart from adverse remodeling through inhibiting key pro-fibrotic signaling pathways. These findings suggest that Smad1 activation may be a promising strategy to restrain cardiac fibrosis in infarcted and failing hearts.