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(Circulation Research. 2006;98:785.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Desensitization of Platelet-Derived Growth Factor Receptor-ß by Oxidized Lipids in Vascular Cells and Atherosclerotic Lesions

Prevention by Aldehyde Scavengers

Cecile Vindis, Isabelle Escargueil-Blanc, Meyer Elbaz, Bertrand Marcheix, Marie-Helene Grazide, Koji Uchida, Robert Salvayre, Anne Nègre-Salvayre

From the INSERM U-466 and Biochemistry Department (C.V., I. E.-B., M.E., B.M., M.-H.G., R.S., A.N.-S.), IFR-31, CHU Rangueil, Toulouse, France; and Laboratory of Food and Biodynamics (K.U.), Graduate School of Bioagricultural Sciences, Nagoya University, Japan.

Correspondence to Professor R. Salvayre, Biochimie, INSERM U466, IFR-31, CHU Rangueil, 1, Avenue Jean Poulhès, TSA-50032-31059 Toulouse Cedex 9, France. E-mail salvayre{at}toulouse.inserm.fr

The platelet-derived growth factor receptor-ß (PDGFRß) signaling pathway regulates smooth muscle cell (SMC) migration and proliferation and plays a role in the vascular wall response to injury. Oxidized low-density lipoprotein (oxLDL) in atherosclerotic lesions can activate the PDGFRß pathway, but the long-term effects of oxLDL on PDGFRß function are not well understood. We found that oxLDL induced a dual effect on PDGFRß signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFRß desensitization was not attributable to PDGFRß degradation or changes in localization to the caveolae but instead resulted from decreased PDGF binding and inhibition of PDGFRß tyrosine kinase activity. This inhibition was associated with formation of (4HNE)– and acrolein–PDGFRß adducts and was mimicked by preincubation of cells with 4HNE. These PDGFRß adducts were also detected in aortae of apolipoprotein-deficient mice and hypercholesterolemic rabbits and in human carotid plaques. The aldehyde scavengers DNPH and Hydralazine prevented both oxLDL- and 4HNE-induced structural modification and PDGFRß signaling dysfunction in cells and in vivo. OxLDL inhibition of PDGF signaling may contribute to defective SMC proliferation and decrease the stability of a vulnerable plaque.

Key Words: atherosclerosis • oxidized LDL • PDGF receptor • cell proliferation • signaling

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