doi: 10.1161/hc4001.097179
(Circulation. 2001;104:1814.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor ß-Receptor Pathway
From INSERM U-466 and the Biochemistry Department, IFR-31, CHU Rangueil, Toulouse, France (I.E.-B., R.S., N.V., A.N.-S.); Institute of Medical Biochemistry, Karl-Franzens Universität, Graz, Austria (G.J.); INSERM U-397, IFR-31, CHU Rangueil, Toulouse, France (B.D., J.-F.A.); and the Department of Gynecology and Obstetrics, Emory University, Atlanta, Ga (S.P.).
Correspondence to Dr A. Negre-Salvayre, Biochimie and INSERM U-466-CHU Rangueil, Avenue Jean-Poulhès 31403-Toulouse Cedex-4 France. E-mail anesalv{at}rangueil.inserm.fr
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 ß (PDGFRß), 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 PDGFRß signaling pathway, as shown by PDGFRß tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFRß activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFRß activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFRß (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFRß adduct formation and subsequent PDGFRß activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H2O2 (these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal–PDGFRß adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFRß activation may occur during atherogenesis.
Conclusions— MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFRß acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFRß activation in atherosclerotic areas.
Key Words: lipoproteins • platelet-derived factors • atherosclerosis
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