Abstract:Follistatin-like 1 (Fstl1) is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis via regulation of TGF-β and BMP. Reducing Fstl1 in mice reduces bleomycin-induced fibrosis in vivo, offering a potential therapeutic target for progressive lung fibrosis.
“…FSTL1 can activate and increase the expression of TGFβ41. In the present study, we observed that TGFβ, total Smad2/3 and p-Smad2/3 protein levels were increased by exogenous FSTL1 administration.…”
Exercise training has been reported to ameliorate heart dysfunction in both humans and animals after myocardial infarction (MI), but the underlying mechanisms are poorly understood. Follistatin-like1 (FSTL1) is a cardioprotective factor against ischemic injury and is induced in cardiomyocytes and skeletal muscle in ischemic and hypoxic conditions. To test the hypothesis that FSTL1 may be a molecular link between exercise and improved heart function post MI, we subjected MI-rats, induced by left coronary artery ligation, to two modes of exercise: intermittent aerobic exercise (IAE) or mechanical vibration training (MVT), for four weeks and examined the relevance of FSTL1 to exercise-mediated cardiac effects. Exercise improved the functional performance, reduced fibrosis of MI-hearts and induced FSTL1 expression, the TGFβ-Smad2/3 signaling and angiogenesis in myocardium. In gastrocnemius, exercise increased the cross-sectional area of myocytes and FSTL1 expression. Importantly, exercise increased circulating FSTL1 levels, which were positively correlated with the skeletal muscle FSTL1 expression and negatively correlated with heart fibrosis. Overall, the IAE was more effective than that of MVT in cardioprotection. Finally, exogenous FSTL1 administration directly improved angiogenesis as well as functionality of post-MI hearts. Taken together, we have demonstrated that FSTL1 is a potential mediator of exercise-induced cardioprotection in post-MI rats.
“…FSTL1 can activate and increase the expression of TGFβ41. In the present study, we observed that TGFβ, total Smad2/3 and p-Smad2/3 protein levels were increased by exogenous FSTL1 administration.…”
Exercise training has been reported to ameliorate heart dysfunction in both humans and animals after myocardial infarction (MI), but the underlying mechanisms are poorly understood. Follistatin-like1 (FSTL1) is a cardioprotective factor against ischemic injury and is induced in cardiomyocytes and skeletal muscle in ischemic and hypoxic conditions. To test the hypothesis that FSTL1 may be a molecular link between exercise and improved heart function post MI, we subjected MI-rats, induced by left coronary artery ligation, to two modes of exercise: intermittent aerobic exercise (IAE) or mechanical vibration training (MVT), for four weeks and examined the relevance of FSTL1 to exercise-mediated cardiac effects. Exercise improved the functional performance, reduced fibrosis of MI-hearts and induced FSTL1 expression, the TGFβ-Smad2/3 signaling and angiogenesis in myocardium. In gastrocnemius, exercise increased the cross-sectional area of myocytes and FSTL1 expression. Importantly, exercise increased circulating FSTL1 levels, which were positively correlated with the skeletal muscle FSTL1 expression and negatively correlated with heart fibrosis. Overall, the IAE was more effective than that of MVT in cardioprotection. Finally, exogenous FSTL1 administration directly improved angiogenesis as well as functionality of post-MI hearts. Taken together, we have demonstrated that FSTL1 is a potential mediator of exercise-induced cardioprotection in post-MI rats.
“…5c). This is also in agreement with our recent study using a bleomycin mouse model 24 and suggests that the restored TGF-β1/BMP balance may be the molecular underpinnings for the attenuated fibrogenesis in Fstl1
+/− mice.Figure 5Fstl1 modulates myofibroblast differentiation via facilitating TGF-β1 signaling. ( a ) qRT-PCR analysis of TGF-β1 mRNA expression in lung tissues of Fstl1
+/− and WT mice at indicated time after saline or silica exposure (n = 4 per group; * P < 0.05 by one-way ANOVA followed by Student’s t test).…”
Occupational inhalation of dust, such as crystalline silica, for prolonged periods in the workplace leads to fibrotic lung diseases worldwide. The mechanisms underlying the diseases are unknown, so that no effective treatment exists for these conditions. We found elevated levels of follistatin like 1 (FSTL1) in serum from patients with silicosis and in lungs from silica-induced mouse model. The induced Fstl1 regulated inflammation response via activation of nod-like receptor family, pyrin domain containing 3v (NLRP3) inflammasome-mediated IL-1β production from macrophages. Meanwhile, Fstl1 promoted fibrosis via positive regulation of TGF-β1 signaling. Haploinsufficiency of Fstl1 or blockage of FSTL1 with a neutralizing antibody was protective from silica-induced lung injury in mice in vivo. Our data suggest that Fstl1 plays an important role in lung fibrosis, and may serve as a novel therapeutic target for treatment of silicosis.
“…Our study is the first to use conditional inactivation of Fstl1 in macrophage/myeloid cells to study its influence on a disease phenotype in vivo. Recent studies have used heterozygous Fstl1 +/− deficient mice to demonstrate that inhibiting Fstl1 does not inhibit lung inflammation, but does attenuate bleomycin induced pulmonary fibrosis in mice through a TGFβ dependent pathway 28 . In the study of bleomycin induced pulmonary fibrosis, the cellular source of Fstl1 was fibroblasts 28 a well known mesenchymal source of Fstl1 5 .…”
Section: Discussionmentioning
confidence: 99%
“…Recent studies have used heterozygous Fstl1 +/− deficient mice to demonstrate that inhibiting Fstl1 does not inhibit lung inflammation, but does attenuate bleomycin induced pulmonary fibrosis in mice through a TGFβ dependent pathway 28 . In the study of bleomycin induced pulmonary fibrosis, the cellular source of Fstl1 was fibroblasts 28 a well known mesenchymal source of Fstl1 5 . Our study differs from the study of bleomycin induced pulmonary fibrosis in that we demonstrate that in chronic allergen induced asthma, non-mesenchymal cells such as macrophages (not considered a significant source of Fstl1) are a significant source of Fstl1, that inhibiting Fstl1 inhibits allergen induced airway eosinophilic inflammation (no effect on inhibiting bleomycin induced lung inflammation), and that the downstream pathway of Fstl1 in macrophages is OSM (in bleomycin model it is TGFβ).…”
Chronic asthma is associated with airway remodeling and decline in lung function. Here we show that follistatin like 1 (Fstl1), a mediator not previously associated with asthma is highly expressed by macrophages in the lungs of severe human asthmatics. Chronic allergen challenged Lys-Cretg/Fstl1Δ/Δ mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM) a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, while administration of an anti-OSM antibody blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/oncostatin M pathway may be a novel pathway to inhibit airway remodeling in severe human asthma.
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