TY - JOUR
T1 - Role of von Hippel-Lindau protein in fibroblast proliferation and fibrosis
AU - Zhou, Qiyuan
AU - Pardo, Annie
AU - Königshoff, Melanie
AU - Eickelberg, Oliver
AU - Budinger, G. R.Scott
AU - Thavarajah, Krishna
AU - Gottardi, Cara J.
AU - Jones, Jonathan
AU - Varga, John
AU - Selman, Moises
AU - Sznajder, Jacob I.
AU - Raj, J. Usha
AU - Zhou, Guofei
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - Extracellular matrix
KW - Focal adhesion kinase
KW - Idiopathic pulmonary fibrosis
KW - Integrin α5β1
UR - http://www.scopus.com/inward/record.url?scp=80052669057&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052669057&partnerID=8YFLogxK
U2 - 10.1096/fj.10-177824
DO - 10.1096/fj.10-177824
M3 - Article
C2 - 21642472
AN - SCOPUS:80052669057
VL - 25
SP - 3032
EP - 3044
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 9
ER -