title: Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture.
abstract: 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.
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Sonomi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Kyriakos N
authors.initials: KN
authors.lastname: Papanicolaou
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Soichi
authors.initials: S
authors.lastname: Sano
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Asaumi
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Maurice J
authors.initials: MJ
authors.lastname: van den Hoff
authors.affiliation: Molecular Cardiovascular Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.affiliation: Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Recchia
authors.affiliation: Department of Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA kxwalsh@bu.edu.
authors.forename: Kenneth
authors.identifier: 0000-0001-7580-2276
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D010450:Endopeptidases; D005347:Fibroblasts / Q000502:physiology*; D038681:Follistatin; D038702:Follistatin-Related Proteins / Q000172:deficiency / Q000378:metabolism*; D018093:Gelatinases; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology*; D012421:Rupture / Q000473:pathology*; D012697:Serine Endopeptidases; D016019:Survival Analysis; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D038681:Follistatin; D038702:Follistatin-Related Proteins; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: cardiokine; fibrosis; infarct healing; myocardial infarction