LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis

Enomoto, Yasunori; Matsushima, Sayomi; Shibata, Kiyoshi; Aoshima, Yoichiro; Yagi, Haruna; Meguro, Shiori; Kawasaki, Hideya; Kosugi, Isao; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Inui, Naoki; Suda, Takafumi; Iwashita, Toshihide

doi:10.1042/cs20180435

Cited by 45 publications

(52 citation statements)

References 43 publications

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“…The latent transforming growth factor beta binding protein 2 (Ltbp2) gene encodes a protein that belongs to the latent TGF-β-binding protein (LTBP) family, and this protein shares similarities with the fibrillins. Ltbp2 is a potential prognostic blood biomarker that may reflect the level of differentiation of lung fibroblasts into myofibroblasts in idiopathic pulmonary fibrosis (41). Peptidase domain containing associated with muscle regeneration 1 (Pamr1) is a putative tumor suppressor that is frequently inactivated by promoter hyper-methylation in breast cancer tissues (42).…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes and preliminary validations in cardiac pathological remodeling induced by transverse aortic constriction

et al. 2019

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Cardiac remodeling predisposes to heart failure if the burden is unresolved, and heart failure is an important cause of mortality in humans. The aim of the present study was to identify the key genes involved in cardiac pathological remodeling induced by pressure overload. Gene expression profiles of the GSE5500, GSE18224, GSE36074 and GSE56348 datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs), defined as |log 2 FC|>1 (FC, fold change) and an adjusted P-value of <0.05, were screened using the R software with the limma package. Gene ontology enrichment analysis was performed and a protein-protein interaction (PPI) network of the DEGs was constructed. A cardiac remodeling model induced by transverse aortic constriction (TAC) was established. Furthermore, consistent DEGs were further validated using reverse transcription-quantitative polymerase chain reaction (RT-PCR) analysis, western blotting and immunohistochemistry in the ventricular tissue samples after TAC or sham operation. A total of 24 common DEGs were identified (23 significantly upregulated and 1 downregulated), of which 9 genes had been previously confirmed to be directly involved in cardiac remodeling. Hence, the level of expression of the other 15 genes was detected in subsequent studies via RT-PCR. Based on the results of the PPI network analysis and RT-PCR, we further detected the protein levels of Itgbl1 and Asporin, which were consistent with the results of bioinformatics analysis and RT-PCR. The expression of Itgbl1, Aspn, Fstl1, Mfap5, Col8a1, Ltbp2, Mfap4, Pamr1, Cnksr1, Aqp8, Meox1, Gdf15 and Srpx was found to be upregulated in a mouse model of cardiac remodeling, while that of Retnla was downregulated. Therefore, the present study identified the key genes implicated in cardiac remodeling, aiming to provide new insight into the underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

Identification of differentially expressed genes and preliminary validations in cardiac pathological remodeling induced by transverse aortic constriction

et al. 2019

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“…It is mainly expressed in the lung, skin, and large blood vessels ( Wang et al, 2018 ). LTBP2 has various biological functions involving the ECM composition and plays a vital role in elastic fibers and cell adhesion ( Enomoto et al, 2018 ). Interestingly, we detected high mRNA and protein expression of LTBP2 in lungs of the PF mouse model and TGF-β1-stimulated mouse and human fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, we detected high mRNA and protein expression of LTBP2 in lungs of the PF mouse model and TGF-β1-stimulated mouse and human fibroblasts. A previous study has reported that LTBP2 is secreted from lung myofibroblasts and may reflect the level of differentiation of lung fibroblasts into myofibroblasts in IPF ( Enomoto et al, 2018 ). This hints that LTBP2 is a biomarker of cell identity in myofibroblasts, consistent with the super-enhancer’s function.…”

Section: Discussionmentioning

confidence: 99%

Identification of Potential Pathogenic Super-Enhancers-Driven Genes in Pulmonary Fibrosis

Zhao

et al. 2021

Front. Genet.

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Abnormal fibroblast differentiation into myofibroblast is a crucial pathological mechanism of pulmonary fibrosis (PF). Super-enhancers, a newly discovered cluster of regulatory elements, are regarded as the regulators of cell identity. We speculate that abnormal activation of super-enhancers must be involved in the pathological process of PF. This study aims to identify potential pathogenic super-enhancer-driven genes in PF. Differentially expressed genes (DEGs) in PF mouse lungs were identified from a GEO dataset (GDS1492). We collected super-enhancers and their associated genes in human lung fibroblasts and mouse embryonic fibroblasts from SEA version 3.0, a network database that provides comprehensive information on super-enhancers. We crosslinked upregulated DEGs and super-enhancer-associated genes in fibroblasts to predict potential super-enhancer-driven pathogenic genes in PF. A total of 25 genes formed an overlap, and the protein-protein interaction network of these genes was constructed by the STRING database. An interaction network of transcription factors (TFs), super-enhancers, and associated genes was constructed using the Cytoscape software. Gene enrichment analyses, including KEGG pathway and GO analysis, were performed for these genes. Latent transforming growth factor beta (TGF-β) binding protein 2 (LTBP2), one of the predicted super-enhancer-driven pathogenic genes, was used to verify the predicted network’s accuracy. LTBP2 was upregulated in the lungs of the bleomycin-induced PF mouse model and TGF-β1-stimulated mouse and human fibroblasts. Myc is one of the TFs binding to the LTBP2 super-enhancer. Knockout of super-enhancer sequences with a CRISPR/Cas9 plasmid or inhibition of Myc all decreased TGF-β1-induced LTBP2 expression in NIH/3 T3 cells. Identifying and interfering super-enhancers might be a new way to explore possible therapeutic methods for PF.

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“…Conversely, serum PRDX4 protein and LDH levels showed better AUC profiles, obtained using ROC curves, to distinguish AE-IPF from S-IPF than serum KL-6 and SP-D levels. A recent report demonstrated that HSP47 (47 kDa) may be a potential biomarker for distinguishing AE-IPF from S-IPF, and monomeric periostin (90 kDa) and latent TGF-β binding protein-2 (195–240 kDa) are useful for predicting poor prognosis in patients with IPF [9, 30]. The molecular weight of these biomarkers is smaller than that of KL-6 (> 200 kDa) [31], and considering that the molecular weight is associated with biomarker profiles [10, 29], the small molecular weight of PRDX4 (34 kDa) [20] may explain its better profile as a marker for detecting AE-IPF.…”

Section: Discussionmentioning

confidence: 99%

The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis

et al. 2019

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BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear.MethodsSerum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration.ResultsSerum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice.ConclusionsPRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

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LTBP2 is secreted from lung myofibroblasts and is a potential biomarker for idiopathic pulmonary fibrosis

Cited by 45 publications

References 43 publications

Identification of differentially expressed genes and preliminary validations in cardiac pathological remodeling induced by transverse aortic constriction

Identification of differentially expressed genes and preliminary validations in cardiac pathological remodeling induced by transverse aortic constriction

Identification of Potential Pathogenic Super-Enhancers-Driven Genes in Pulmonary Fibrosis

The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis

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