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J. Biol. Chem., Vol. 275, Issue 51, 40561-40567, December 22, 2000
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From the Hepatic stellate cells (HSC) undergo activation
toward myofibroblast-like cells during early stages of liver injury
associated with fibrogenesis. Platelet-derived growth factor (PDGF),
particularly its BB isoform, has been identified as the most potent
mitogen for HSC. 4-Hydroxy-2,3-nonenal and related
4-hydroxy-2,3-alkenals (HAKs) have been suggested to modulate the
process of HSC activation. In this study we investigated the
relationship between HAKs and PDGF receptor activation in human HSC. By
employing noncytotoxic concentrations (10
Interaction between 4-Hydroxy-2,3-alkenals and the
Platelet-derived Growth Factor-
Receptor
REDUCED TYROSINE PHOSPHORYLATION AND DOWNSTREAM SIGNALING IN
HEPATIC STELLATE CELLS*
,,
,
Dipartimento di Medicina ed Oncologia
Sperimentale, Università di Torino, 10125 Torino, the
¶ Dipartimento di Medicina Interna, Università di Firenze,
50134 Firenze, and the Dipartimento di Scienze Mediche,
Università A. Avogadro, 28100 Novara, Italy
6
M) of HAKs, we observed a significant inhibition of
PDGF-BB-dependent DNA synthesis. HAKs inhibited relevant
pathways of PDGF-BB-dependent mitogenic signaling,
including autophosphorylation of PDGF receptor (PDGF-R) 
subunits
and activation of phosphatidylinositol 3-kinase and extracellular
regulated kinases 1/2. Inhibition of DNA synthesis was reversible, and
recovery of PDGF-mediated mitogenic signaling occurred within 24-48 h
and was associated with HAKs-induced up-regulation of PDGF-R gene
expression. 4-Hydroxy-2,3-nonenal, used as a model HAK, inhibited the
intrinsic tyrosine kinase activity associated with the PDGF-R subunit, whereas binding of PDGF to its receptor was unaffected. This
study identifies a novel regulatory mechanism of reactive aldehydes on
PDGF receptor signaling and biologic actions, which may be relevant in
several pathophysiological conditions, including liver fibrosis.
*
This work was supported by Ministero dell'Università
e della Ricerca Scientifica e Tecnologica (Rome, Italy), by the
National Project of Molecular and Cellular Biology of Hepatic Fibrosis, and by the Italian Liver Foundation (Florence, Italy).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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