TY - JOUR
T1 - Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture
AU - Maruyama, Sonomi
AU - Nakamura, Kazuto
AU - Papanicolaou, Kyriakos N.
AU - Sano, Soichi
AU - Shimizu, Ippei
AU - Asaumi, Yasuhide
AU - van den Hoff, Maurice J.
AU - Ouchi, Noriyuki
AU - Recchia, Fabio Anastasio
AU - Walsh, Kenneth
N1 - Funding Information:
This work was supported by NIH grants HL081587, HL116591, HL120160, and HL126141 and Takeda Pharmaceuticals (K. Walsh, S. Maruyama). F.A. Recchia was supported by NIH grants HL74237 and HL108213. S. Maruyama was also supported by a Postdoctoral Research Fellowship in Cardiology by Japan Heart Foundation and Bayer (Japan). We thank Francesca Seta for consultation on the polarized microscopy. We are also grateful to Rouan Yao, Taina Rokotuiveikau, Matthew Phillippo, Maria Angeles Zuriaga Herrero, Reina Kobayashi, Miho Sano, and Blake Jardin for their assistance in mouse husbandry.
Publisher Copyright:
© 2016 The Authors. Published under the terms of the CC BY 4.0 license
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type-specific regulation of Fstl1 and its function in a murine model of MI. Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area compared to cardiac myocytes. The conditional ablation of Fstl1 in S100a4-expressing fibroblast lineage cells (Fstl1-cfKO mice) led to a reduction in injury-induced Fstl1 expression and increased mortality due to cardiac rupture during the acute phase. Cardiac rupture was associated with a diminished number of myofibroblasts and decreased expression of extracellular matrix proteins. The infarcts of Fstl1-cfKO mice displayed weaker birefringence, indicative of thin and loosely packed collagen. Mechanistically, the migratory and proliferative capabilities of cardiac fibroblasts were attenuated by endogenous Fstl1 ablation. The activation of cardiac fibroblasts by Fstl1 was mediated by ERK1/2 but not Smad2/3 signaling. This study reveals that Fstl1 is essential for the acute repair of the infarcted myocardium and that stimulation of early fibroblast activation is a novel function of Fstl1.
AB - Follistatin-like 1 (Fstl1) is a secreted protein that is acutely induced in heart following myocardial infarction (MI). In this study, we investigated cell type-specific regulation of Fstl1 and its function in a murine model of MI. Fstl1 was robustly expressed in fibroblasts and myofibroblasts in the infarcted area compared to cardiac myocytes. The conditional ablation of Fstl1 in S100a4-expressing fibroblast lineage cells (Fstl1-cfKO mice) led to a reduction in injury-induced Fstl1 expression and increased mortality due to cardiac rupture during the acute phase. Cardiac rupture was associated with a diminished number of myofibroblasts and decreased expression of extracellular matrix proteins. The infarcts of Fstl1-cfKO mice displayed weaker birefringence, indicative of thin and loosely packed collagen. Mechanistically, the migratory and proliferative capabilities of cardiac fibroblasts were attenuated by endogenous Fstl1 ablation. The activation of cardiac fibroblasts by Fstl1 was mediated by ERK1/2 but not Smad2/3 signaling. This study reveals that Fstl1 is essential for the acute repair of the infarcted myocardium and that stimulation of early fibroblast activation is a novel function of Fstl1.
KW - cardiokine
KW - fibrosis
KW - infarct healing
KW - myocardial infarction
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U2 - 10.15252/emmm.201506151
DO - 10.15252/emmm.201506151
M3 - Article
C2 - 27234440
AN - SCOPUS:84979983331
VL - 8
SP - 949
EP - 966
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 8
ER -