Desensitization of platelet-derived growth factor receptor-beta by oxidized lipids in vascular cells and atherosclerotic lesions: prevention by aldehyde scavengers.
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.
Vindis
Cecile
C
INSERM U-466, IFR-31, Biochemistry Department, IFR-31, CHU Rangueil, Toulouse, France.
Escargueil-Blanc
Isabelle
I
Elbaz
Meyer
M
Marcheix
Bertrand
B
Grazide
Marie-Helene
MH
Uchida
Koji
K
Salvayre
Robert
R
Nègre-Salvayre
Anne
A
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
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