Induction of galectin-1 by TGF-β1 accelerates fibrosis through enhancing nuclear retention of Smad2

Lim, Min Jin; Ahn, Joon-Woo; Yi, Jianxun; Kim, Mi-Hyoung; Son, Arang; Lee, Sae-lo-oom; Lim, Dae‐Seog; Kim, Sung Soo; Kang, Mi Ae; Han, Young‐Soo; Song, Jie‐Young

doi:10.1016/j.yexcr.2014.06.001

Cited by 51 publications

(23 citation statements)

References 38 publications

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“…TGF-β has a complex role, its downstream effects involve both apoptosis and cell proliferation, and these end results are cell type-dependent [42]. Increase in TGF-β, α-SMA and collagen have been documented in fibrotic response [43]. When quantified in this study, cytokines IL6 and TGF-β were significantly increased in restenotic plaques.…”

Section: Discussionmentioning

confidence: 68%

Enhanced neointimal fibroblast, myofibroblast content and altered extracellular matrix composition: Implications in the progression of human peripheral artery restenosis

Ramanathan¹,

Purushothaman²,

Purushothaman

et al. 2016

Atherosclerosis

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Background and aims Neointimal cellular proliferation of fibroblasts and myofibroblasts is documented in coronary artery restenosis, however, their role in peripheral arterial disease (PAD) restenosis remains unclear. Our aim was to investigate the role of fibroblasts, myofibroblasts, and collagens in restenotic PAD. Methods Nineteen PAD restenotic plaques were compared with 13 de novo plaques. Stellate cells (H&E), fibroblasts (FSP-1), myofibroblasts (α-actin/vimentin/FSP-1), cellular proliferation (Ki-67), and apoptosis (caspase-3 with poly ADP-ribose polymerase) were evaluated by immunofluorescence. Collagens were evaluated by picro-sirius red stain with polarization microscopy. Smooth muscle myosin heavy chain (SMMHC), IL-6 and TGF-β cytokines were analyzed by immunohistochemistry. Results Restenotic plaques demonstrated increased stellate cells (2.7 ± 0.15 vs. 1.3 ± 0.15) fibroblasts (2282.2 ± 85.9 vs. 906.4 ± 134.5) and myofibroblasts (18.5 ± 1.2 vs. 10.6 ± 1.0) p = 0.0001 for all comparisons. In addition, fibroblast proliferation (18.4% ± 1.2 vs. 10.4% ± 1.1; p = 0.04) and apoptosis (14.6% ± 1.3 vs. 11.2% ± 0.6; p = 0.03) were increased in restenotic plaques. Finally, SMMHC (2.6 ± 0.12 vs. 1.4 ± 0.15; p = 0.0001), type III collagen density (0.33 ± 0.06 vs. 0.17 ± 0.07; p = 0.0001), IL-6 (2.08 ± 1.7 vs. 1.03 ± 2.0; p = 0.01), and TGF-β (1.80 ± 0.27 vs. 1.11 ± 0.18; p = 0.05) were increased in restenotic plaques. Conclusions Our study suggests proliferation and apoptosis of fibroblast and myofibroblast with associated increase in type III collagen may play a role in restenotic plaque progression. Understanding pathways involved in proliferation and apoptosis in neointimal cells, may contribute to future therapeutic interventions for the prevention of restenosis in PAD.

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Section: Discussionmentioning

confidence: 68%

Enhanced neointimal fibroblast, myofibroblast content and altered extracellular matrix composition: Implications in the progression of human peripheral artery restenosis

Ramanathan¹,

Purushothaman²,

Purushothaman

et al. 2016

Atherosclerosis

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“…29 Further, galectin-1 expression is induced by TGF- β /SMAD signaling in lung fibroblasts, accelerating PF. 30 As FAK1 knockdown dampened SMAD3 activation in hypoxia (Figures 4c and d), we tested whether SMAD3 and FAK1 can regulate hypoxia-induced transcription of galectin-1. Indeed, FAK1 knockdown and SMAD3 inhibition reduced hypoxia-induced galectin-1 mRNA levels (Figures 5b and c), indicating a functional crosstalk of SMAD3 and FAK1 signaling to regulate galectin-1 activation in hypoxic lung epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

et al. 2017

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Idiopathic pulmonary fibrosis (IPF) is characterized by lung remodeling arising from epithelial injury, aberrant fibroblast growth, and excessive deposition of extracellular matrix. Repeated epithelial injury elicits abnormal wound repair and lung remodeling, often associated with alveolar collapse and edema, leading to focal hypoxia. Here, we demonstrate that hypoxia is a physiological insult that contributes to pulmonary fibrosis (PF) and define its molecular roles in profibrotic activation of lung epithelial cells. Hypoxia increased transcription of profibrotic genes and altered the proteomic signatures of lung epithelial cells. Network analysis of the hypoxic epithelial proteome revealed a crosstalk between transforming growth factor-β1 and FAK1 (focal adhesion kinase-1) signaling, which regulated transcription of galectin-1, a profibrotic molecule. Galectin-1 physically interacted with and activated FAK1 in lung epithelial cells. We developed a novel model of exacerbated PF wherein hypoxia, as a secondary insult, caused PF in mice injured with subclinical levels of bleomycin. Hypoxia elevated expression of phosphorylated FAK1, galectin-1, and α-smooth muscle actin and reduced caspase-3 activation, suggesting aberrant injury repair. Galectin-1 inhibition caused apoptosis in the lung parenchyma and reduced FAK1 activation, preventing the development of hypoxia-induced PF. Galectin-1 inhibition also attenuated fibrosis-associated lung function decline. Further, galectin-1 transcript levels were increased in the lungs of IPF patients. In summary, we have identified a profibrotic role of galectin-1 in hypoxia signaling driving PF.

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“…The abnormal activation of fibroblasts is one of the major factors driving fibrotic progression in IPF [22–24]. TGFβ activates fibroblasts and enhances collagen synthesis and extracellular matrix deposition [25–27].…”

Section: Discussionmentioning

confidence: 99%

miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway

et al. 2017

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BackgroundMicroRNAs are a group of small RNAs that regulate gene expression at the posttranscriptional level. They regulate almost every aspect of cellular processes. In this study, we investigated whether miR-27b regulates pulmonary fibroblast activation.ResultsWe found that miR-27b was down-regulated in fibrotic lungs and fibroblasts from an experimental mouse model of pulmonary fibrosis. The overexpression of miR-27b with a lentiviral vector inhibited TGFβ1-stimulated mRNA expression of collagens (COL1A1, COL3A1, and COL4A1) and alpha-smooth muscle actin, and protein expression of Col3A1 and alpha-smooth muscle actin in LL29 human pulmonary fibroblasts. miR-27b also reduced contractile activity of LL29. TGFβ receptor 1 and SMAD2 were identified as the targets of miR-27b by 3’-untranslated region luciferase reporter and western blotting assays.ConclusionsOur results suggest that miR-27b is an anti-fibrotic microRNA that inhibits fibroblast activation by targeting TGFβ receptor 1 and SMAD2. This discovery may provide new targets for therapeutic interventions of idiopathic pulmonary fibrosis.

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Induction of galectin-1 by TGF-β1 accelerates fibrosis through enhancing nuclear retention of Smad2

Cited by 51 publications

References 38 publications

Enhanced neointimal fibroblast, myofibroblast content and altered extracellular matrix composition: Implications in the progression of human peripheral artery restenosis

Enhanced neointimal fibroblast, myofibroblast content and altered extracellular matrix composition: Implications in the progression of human peripheral artery restenosis

Galectin-1 inhibition attenuates profibrotic signaling in hypoxia-induced pulmonary fibrosis

miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway

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