Role of von Hippel-Lindau protein in fibroblast proliferation and fibrosis

TitleRole of von Hippel-Lindau protein in fibroblast proliferation and fibrosis
Publication TypeJournal Article
Year of Publication2011
AuthorsZhou Q, Pardo A, Königshoff M, Eickelberg O, Budinger GRScott, Thavarajah K, Gottardi CJ, Jones J, Varga J, Selman M, Sznajder JI, J Raj U, Zhou G
JournalFASEB J
Volume25
Issue9
Pagination3032-44
Date Published2011 Sep
ISSN1530-6860
KeywordsAnimals, Antibiotics, Antineoplastic, Bleomycin, Cell Line, Cell Proliferation, Fibroblasts, Fibronectins, Humans, Idiopathic Pulmonary Fibrosis, Integrin alpha5, Integrin alpha5beta1, Mice, Mice, Inbred C57BL, Specific Pathogen-Free Organisms, Transforming Growth Factor beta1, Up-Regulation, Von Hippel-Lindau Tumor Suppressor Protein
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.

DOI10.1096/fj.10-177824
Alternate JournalFASEB J.
PubMed ID21642472
PubMed Central IDPMC3157679
Grant ListAR-042309 / AR / NIAMS NIH HHS / United States
HL-071643 / HL / NHLBI NIH HHS / United States
HL-093014 / HL / NHLBI NIH HHS / United States
R01 ES013995 / ES / NIEHS NIH HHS / United States