title: Role of von Hippel-Lindau protein in fibroblast proliferation and fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by exaggerated fibroblast proliferation and accumulation of collagens and fibronectin. The extracellular fibronectin and collagen network is regulated by von Hippel-Lindau protein (pVHL). However, it is unknown whether pVHL contributes to pulmonary fibrosis. We found that lungs from patients with IPF expressed increased levels of pVHL in fibroblastic foci. Bleomycin treatment also induced pVHL in lung fibroblasts, but not in alveolar type II cells. Overexpression of pVHL increased lung fibroblast proliferation, protein abundance of fibronectin and collagen, and extracellular fibronectin. In addition, overexpression of pVHL induced expression of the α5 integrin subunit. Overexpression of pVHL did not alter hypoxia-inducible factor luciferase reporter activity and mRNA expression of vascular endothelial growth factor. Fibroblasts overexpressing pVHL were more sensitive to RGD peptide-mediated reduction in proliferation. Activating α5 and β1 integrin increased proliferation of fibroblasts overexpressing pVHL and those cells were more resistant to the inhibition of α5 integrin. Overexpression of pVHL also increased activation of focal adhesion kinase (FAK). Moreover, suppression of pVHL prevented TGF-β1-induced proliferation of mouse embryonic fibroblasts. Taken together, our results indicate that elevated expression of pVHL results in the aberrant fibronectin expression, activation of integrin/FAK signaling, fibroblast proliferation, and fibrosis.
authors.affiliation: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Krishna
authors.initials: K
authors.lastname: Thavarajah
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jones
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.forename: Guofei
authors.initials: G
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013047:Specific Pathogen-Free Organisms; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D005353:Fibronectins; D039482:Integrin alpha5; D039081:Integrin alpha5beta1; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human