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

Qiyuan Zhou, Annie Pardo, Melanie Königshoff, Oliver Eickelberg, G. R.Scott Budinger, Krishna Thavarajah, Cara J. Gottardi, Jonathan Jones, John Varga, Moises Selman, Jacob I. Sznajder, J. Usha Raj, Guofei Zhou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3032-3044
Number of pages13
JournalFASEB Journal
Volume25
Issue number9
DOIs
StatePublished - Sep 2011

Keywords

  • Extracellular matrix
  • Focal adhesion kinase
  • Idiopathic pulmonary fibrosis
  • Integrin α5β1

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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