Interaction between 4-hydroxy-2,3-alkenals and the platelet-derived growthfactor-beta receptor - Reduced tyrosine phosphorylation and downstream signaling in hepatic stellate cells

Hepatic stellate cells (HSC) undergo activation toward myofibroblast-like c ells during early stages of liver injury associated with fibrogenesis. Plat elet-derived growth factor (PDGF), particularly its BE isoform, has been id entified as the most potent mitogen for HSC. 4-Hydroxy-2,3-nonenal and rela ted 4-hydroxy-2,3-alkenals (HAKs) have been suggested to modulate the proce ss of HSC activation. In this study we investigated the relationship betwee n HAKs and PDGF receptor activation in human HSC. By employing noncytotoxic concentrations (10(-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 rec eptor (PDGF-R) beta subunits and activation of phosphatidylinositol 3-kinas e and extracellular regulated kinases 1/2. Inhibition of DNA synthesis was reversible, and recovery of PDGF-mediated mitogenic signaling occurred with in 24-48 h and was associated with HAKs-induced up-regulation of PDGF-R bet a gene expression. 4-Hydroxy-2,3-nonena1, used as a model HAK, inhibited th e intrinsic tyrosine kinase activity associated with the PDGF-R beta subuni t, whereas binding of PDGF to its receptor was unaffected. This study ident ifies a novel regulatory mechanism of reactive aldehydes on PDGF receptor s ignaling and biologic actions, which may be relevant in several pathophysio logical conditions, including liver fibrosis.