Interaction between 4-Hydroxy-2,3-alkenals and the Platelet-derived Growth Factor-β Receptor
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 rela...
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Published in | The Journal of biological chemistry Vol. 275; no. 51; p. 40561 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
22.12.2000
|
Online Access | Get full text |
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Summary: | 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 â6
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) β 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 24â48 h and was associated with HAKs-induced up-regulation of PDGF-R β gene expression.
4-Hydroxy-2,3-nonenal, used as a model HAK, inhibited the intrinsic tyrosine kinase activity associated with the PDGF-R β
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. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M007694200 |