Mildly oxidized LDL induces activation of platelet-derived growth factor beta-receptor pathway

Background-Mildly oxidized LDL (moxLDL) is thought to play a role in athero genesis. MoxLDL induces derivatization of cell proteins and triggers a vari ety of intracellular signaling. We aimed to investigate whether moxLDL-indu ced protein derivatization may influence the activity of platelet-derived g rowth factor receptor beta (PDGFR beta), a tyrosine kinase receptor of majo r importance in vascular biology and atherogenesis. Methods and Results-In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFR beta signaling pathway, as shown by PDGFR beta tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFR beta activation can be summarized as follows. Oxidized lipids from m oxLDL trigger two phases of PDGFR beta activation involving two separate me chanisms, as shown by experiments on cultured cells (in situ) and on immuno purified PDGFR beta (in vitro): (1) the first phase may be mediated by 4-hy droxynonenal, which induces PDGFR beta adduct formation and subsequent PDGF R beta activation (antioxidant-insensitive step); (2) the second phase invo lves ceramide-mediated generation of H2O2 (these steps being inhibited by t osylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal-PDGFR beta adducts are also detected in atheroscle rotic aortas, it is suggested that this novel mechanism of moxLDL-induced P DGFR beta activation may occur during atherogenesis. Conclusions-MoxLDL acts as a local autoparacrine mediator in the vascular w all, and PDGFR beta acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFR beta activation in ath erosclerotic areas.