title: Ltbp4 regulates Pdgfrβ expression via TGFβ-dependent modulation of Nrf2 transcription factor function.
abstract: Latent transforming growth factor beta binding protein 4 (LTBP4) belongs to the fibrillin/LTBP family of proteins and plays an important role as a structural component of extracellular matrix (ECM) and local regulator of TGFβ signaling. We have previously reported that Ltbp4S knock out mice (Ltbp4S-/-) develop centrilobular emphysema reminiscent of late stage COPD, which could be partially rescued by inactivating the antioxidant protein Sestrin 2 (Sesn2). More recent studies showed that Sesn2 knock out mice upregulate Pdgfrβ-controlled alveolar maintenance programs that protect against cigarette smoke induced pulmonary emphysema. Based on this, we hypothesized that the emphysema of Ltbp4S-/- mice is primarily caused by defective Pdgfrβ signaling. Here we show that LTBP4 induces Pdgfrβ signaling by inhibiting the antioxidant Nrf2/Keap1 pathway in a TGFβ-dependent manner. Overall, our data identified Ltbp4 as a major player in lung remodeling and injury repair.
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Tomasovic
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Kurrle
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Wempe
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: De-Zolt
authors.affiliation: Excellence Cluster Cardiopulmonary System (ECCPS), Justus-Liebig-University Giessen, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), D-35392 Giessen, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Scheibe
authors.affiliation: Research Programs Unit and Transplantation Laboratory, Haartman Institute, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Serchinger
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schnütgen
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
authors.forename: Duran
authors.initials: D
authors.lastname: Sürün
authors.affiliation: Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Sterner-Kock
authors.affiliation: Excellence Cluster Cardiopulmonary System (ECCPS), Justus-Liebig-University Giessen, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), D-35392 Giessen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany. Electronic address: melchner@em.uni-frankfurt.de.
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000172:deficiency / Q000235:genetics*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008907:Mink; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010544:Peroxidases; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014333:Tropoelastin / Q000172:deficiency / Q000235:genetics; D000084622:Sestrins
chemical_list: D000072019:Kelch-Like ECH-Associated Protein 1; D053779:Latent TGF-beta Binding Proteins; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D010544:Peroxidases; D020797:Receptor, Platelet-Derived Growth Factor beta; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; C117301:Keap1 protein, mouse; C495636:Nfe2l2 protein, mouse; C529380:Sesn2 protein, mouse; D000084622:Sestrins
keywords: COPD; Emphysema; Ltbp4; Nrf2; Pdgfrβ; ROS; Tgfβ