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https://doi.org/10.1161/res.125.suppl_1.828
Copy DOIJournal: Circulation Research | Publication Date: Aug 2, 2019 |
After myocardial infarction (MI), dead cardiomyocytes are permanently replaced by scar tissue due to the lack of cardiomyocyte regeneration. In response to MI, cardiac fibroblasts (CFs) differentiate into myofibroblasts which possess highly organized smooth muscle α-actin (αSMA) stress fibers and secrete a large amount of extracellular matrix (ECM) proteins, essential for the post-MI infarct scar formation. It is well known that the accumulated ECM in the infarct scar stabilize the scar and prevents cardiac rupture. However, the functional role of αSMA stress fiber itself in CF-derived myofibroblasts is still largely unknown besides the wide use of it as a marker of myofibroblast differentiation. Our recent work demonstrated that during myofibroblast differentiation of CFs post-MI, the expression of αSMA reaches a peak a few days earlier than genes encoding ECM proteins. Myofibroblasts then lose αSMA expression and differentiate to the newly identified matrifibrocytes as the infarct scar becomes increasingly stable. These facts suggest a more important role of αSMA stress fibers than ECM proteins in the tissue healing process in early phase post-MI, possibly through providing a support lattice which in turn strengthens the infarcted myocardium. To test our hypothesis, we generated a mouse line with Acta2 (the gene encoding αSMA) flanked by LoxP sites ( Acta2 fl/fl ) to enable cre-mediated Acta2 knockout. Here we show that the loss of Acta2 in CFs leads to enhanced proliferation and reduced contractility upon TGFβ-induced myofibroblast differentiation in vitro . By using a mouse line with tamoxifen-inducible CF-specific Acta2 knockout and CF lineage tracing ( Tcf21 MerCreMer ;Acta2 fl/fl ;R26 GFP ) and a WT control mouse line ( Tcf21 MerCreMer ;R26 GFP ), we identified that CF-specific Acta2 knockout results in significantly exacerbated post-MI cardiac function, increased cardiac rupture incidence, and enhanced fibrosis. More lineage tracing experiments and transcriptome analyses are being conducted to better decipher the impact of Acta2 knockout on CF physiology and post-MI tissue healing.
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