Mildly oxidized LDL induces activation of platelet-derived growth factor beta-receptor pathway.
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 beta (PDGFRbeta), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis.


RESULTS
In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFRbeta signaling pathway, as shown by PDGFRbeta tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFRbeta activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFRbeta activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFRbeta (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which induces PDGFRbeta adduct formation and subsequent PDGFRbeta activation (antioxidant-insensitive step); (2) the second phase involves ceramide-mediated generation of H(2)O(2) (these steps being inhibited by tosylphenylalanylchloromethylketone, an inhibitor of ceramide formation, and by antioxidant BHT, exogenous catalase, or overexpressed human catalase). Because 4-hydroxynonenal-PDGFRbeta adducts are also detected in atherosclerotic aortas, it is suggested that this novel mechanism of moxLDL-induced PDGFRbeta activation may occur during atherogenesis.


CONCLUSIONS
MoxLDL acts as a local autoparacrine mediator in the vascular wall, and PDGFRbeta acts as a sensor for both oxidized lipids and oxidative stress. This constitutes a novel mechanism of PDGFRbeta activation in atherosclerotic areas.
Escargueil-Blanc
I
I
INSERM U-466 and the Biochemistry Department, IFR-31, CHU Rangueil, Toulouse, France.
Salvayre
R
R
Vacaresse
N
N
Jürgens
G
G
Darblade
B
B
Arnal
J F
JF
Parthasarathy
S
S
Nègre-Salvayre
A
A
D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D019898:Autocrine Communication; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D004036:Diet, Atherogenic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D018942:Macrolides; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013109:Sphingomyelins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000447:Aldehydes; D000900:Anti-Bacterial Agents; D000975:Antioxidants; D002518:Ceramides; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D018942:Macrolides; D017382:Reactive Oxygen Species; D013109:Sphingomyelins; C099252:oxidized low density lipoprotein; D014443:Tyrosine; C036978:concanamycin A; D002738:Chloroquine; D006861:Hydrogen Peroxide; D020797:Receptor, Platelet-Derived Growth Factor beta; C027576:4-hydroxy-2-nonenal