Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor β-Receptor Pathway

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Abstract
Background Mildly oxidized LDL (moxLDL) is thought to play a role in atherogenesis. MoxLDL induces derivatization of cell proteins and triggers a variety of intracellular signaling. We aimed to investigate whether moxLDL-induced protein derivatization may influence the activity of platelet-derived growth factor receptor β (PDGFRβ), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis. Methods and Results In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFRβ signaling pathway, as shown by PDGFRβ tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFRβ activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFRβ activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFRβ (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFRβ adduct formation and subsequent PDGFRβ activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H 2 O 2 (these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal–PDGFRβ adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFRβ activation may occur during atherogenesis. Conclusions MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFRβ acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFRβ activation in atherosclerotic areas.