Published online before print March 9, 2006, doi: 10.1161/01.RES.0000216288.93234.c3
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Submitted on August 31, 2005
Revised on February 16, 2006
Accepted on February 23, 2006
Desensitization of Platelet-Derived Growth Factor Receptor-
by Oxidized Lipids in Vascular Cells and Atherosclerotic Lesions. Prevention by Aldehyde Scavengers
Cecile Vindis ;
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.
* To whom correspondence should be addressed. E-mail: salvayre{at}toulouse.inserm.fr.
The platelet-derived growth factor receptor-
(PDGFR) 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 PDGFR pathway, but the long-term effects of oxLDL on PDGFR function are not well understood. We found that oxLDL induced a dual effect on PDGFR signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFR desensitization was not attributable to PDGFR degradation or changes in localization to the calveolae but instead resulted from decreased PDGF binding and inhibition of PDGFR tyrosine kinase activity. This inhibition was associated with formation of (4HNE)- and acrolein-PDGFR adducts and was mimicked by preincubation of cells with 4HNE. These PDGFR 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 PDGFR 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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