title: Desensitization of platelet-derived growth factor receptor-beta by oxidized lipids in vascular cells and atherosclerotic lesions: prevention by aldehyde scavengers.
abstract: The platelet-derived growth factor receptor-beta (PDGFRbeta) 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 PDGFRbeta pathway, but the long-term effects of oxLDL on PDGFRbeta function are not well understood. We found that oxLDL induced a dual effect on PDGFRbeta signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFRbeta desensitization was not attributable to PDGFRbeta degradation or changes in localization to the caveolae but instead resulted from decreased PDGF binding and inhibition of PDGFRbeta tyrosine kinase activity. This inhibition was associated with formation of (4HNE)- and acrolein-PDGFRbeta adducts and was mimicked by preincubation of cells with 4HNE. These PDGFRbeta 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 PDGFRbeta 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.
authors.affiliation: INSERM U-466, IFR-31, Biochemistry Department, IFR-31, CHU Rangueil, Toulouse, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Vindis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Escargueil-Blanc
authors.forename: Meyer
authors.initials: M
authors.lastname: Elbaz
authors.forename: Bertrand
authors.initials: B
authors.lastname: Marcheix
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Grazide
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
authors.forename: Robert
authors.initials: R
authors.lastname: Salvayre
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
mesh_terms: D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D006830:Hydralazine / Q000494:pharmacology*; D006834:Hydrazines / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000447:Aldehydes; D006834:Hydrazines; D008077:Lipoproteins, LDL; D010982:Platelet-Derived Growth Factor; C446799:dinitrophenylhydrazine; C099252:oxidized low density lipoprotein; D006830:Hydralazine; D004247:DNA; D020797:Receptor, Platelet-Derived Growth Factor beta; C027576:4-hydroxy-2-nonenal