Ltbp4 regulates Pdgfrβ expression via TGFβ-dependent modulation of Nrf2 transcription factor function

Ana Tomasovic; Nina Kurrle; Frank Wempe; Silke De-Zolt; Susan Scheibe; Katri Koli; Martin Serchinger; Frank Schnütgen; Duran Sürün; Anja Sterner-Kock; Norbert Weissmann; Harald von Melchner

doi:10.1016/j.matbio.2016.09.006

Ltbp4 regulates Pdgfrβ expression via TGFβ-dependent modulation of Nrf2 transcription factor function

Matrix Biol. 2017 May:59:109-120. doi: 10.1016/j.matbio.2016.09.006. Epub 2016 Sep 17.

Affiliations

¹ Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany.
² 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.
³ Research Programs Unit and Transplantation Laboratory, Haartman Institute, University of Helsinki, 00014, Helsinki, Finland.
⁴ Center for Experimental Medicine, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
⁵ Department of Molecular Hematology, Goethe University Medical School, D-60590 Frankfurt am Main, Germany. Electronic address: [email protected].

PMID: 27645114
DOI: 10.1016/j.matbio.2016.09.006

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.

Keywords: COPD; Emphysema; Ltbp4; Nrf2; Pdgfrβ; ROS; Tgfβ.

MeSH terms

Animals
Cell Line
Epithelial Cells / cytology
Epithelial Cells / metabolism
Extracellular Matrix / metabolism*
Extracellular Matrix / pathology
Fibroblasts / metabolism
Fibroblasts / pathology
Gene Expression Regulation
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism
Latent TGF-beta Binding Proteins / deficiency
Latent TGF-beta Binding Proteins / genetics*
Lung / metabolism
Lung / pathology
Mice
Mice, Knockout
Mink
NF-E2-Related Factor 2 / genetics*
NF-E2-Related Factor 2 / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Peroxidases
Plasmids / chemistry
Plasmids / metabolism
Pulmonary Emphysema / genetics*
Pulmonary Emphysema / metabolism
Pulmonary Emphysema / pathology
Receptor, Platelet-Derived Growth Factor beta / genetics*
Receptor, Platelet-Derived Growth Factor beta / metabolism
Signal Transduction
Transforming Growth Factor beta / genetics*
Transforming Growth Factor beta / metabolism
Tropoelastin / deficiency
Tropoelastin / genetics

Substances

Keap1 protein, mouse
Kelch-Like ECH-Associated Protein 1
Latent TGF-beta Binding Proteins
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Nuclear Proteins
Transforming Growth Factor beta
Tropoelastin
Peroxidases
Sesn2 protein, mouse
Receptor, Platelet-Derived Growth Factor beta