Abstract 229: Follistatin-like 1 Protects Heart From Post-infarction Rupture by Modulating Fibrogenesis

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Rationale: Stress injured heart secretes several cardiokines, including Follistatin-like 1 (Fstl1). Fstl1 is a member of SPARC (secreted protein, acidic and rich in cysteine) family. Fstl1 is strongly overexpressed in ischemic lesion and secreted to blood circulation in acute coronary syndrome. However, roles and mechanisms of Fstl1 in acute myocardial infarction have not been elucidated yet. Methods and results: To assess Fstl1 expression after myocardial infarction (MI), C57BL6 WT mice were underwent LAD permanent ligation. Heart and serum Fstl1 protein levels were increased after day 1 and peaked at 7 days after MI. Immunohistochemistry revealed that fibroblasts and myofibroblasts were the major Fstl1 expressing cells in infarcted area and border zone. However, neither cardiomyocytes nor leukocytes (neutrophil, macrophage) produced Fstl1. Fstl1 deleted mice in fibroblasts lineage (Fstl1-CKO mice) were generated by S100a4cre+/- xFstl1flox/flox mice. S100a4cre-/- xFstl1flox/flox mice were used as control. Fstl1 protein overexpression after MI was reduced 50% in Fstl1-CKO mice heart compared to control mice. Mortality rate after MI was significantly higher in Fstl1-CKO mice than control mice (50%;15 of 30 vs 34.8%; 8 of 23, respectively, log-rank test p=0.031). The majority of causes of death were cardiac rupture in acute period. Cardiac function, blood pressure and severity of inflammation were comparable between Fstl1-CKO and control mice. However, amount of myofibroblasts in Fstl1-CKO heart was significantly less than control mice. Overexpression of extracellular matrix proteins (collagen and fibronectin) in infarcted area was also diminished in Fstl1-CKO mice. Autocrine and paracrine functions of Fstl1 for fibroblasts were assessed in vitro study. Endogenous Fstl1 protein in neonatal rat cardiac fibroblasts (NRCFBs) was knocked down by siRNA fstl1. Migratory activity of NRCFBs was attenuated by Fstl1 ablation. Moreover, Fstl1 augmented TGF-β1 activated Smad2/3 signaling pathway in vivo and vitro. Conclusions: Increased Fstl1after MI prevents heart from cardiac rupture. This study revealed a novel function of Fstl1, promotes extracellular matrix generation to repair infarcted lesion.