Lipid oxidation products and oxidized low-density lipoproteins impair platelet-derived growth factor receptor activity in smooth muscle cells: implication in atherosclerosis.
The platelet-derived growth factor receptor-beta (PDGFRbeta) signaling pathway regulates smooth muscle cell (SMC) migration and proliferation in the vascular wall. Oxidized low-density lipoproteins (oxLDLs) and 4-hydroxynonenal (4-HNE) induce a dual effect on PDGFRbeta signaling. Short-term incubation of SMCs with oxLDLs and 4-HNE induced PDGFRbeta activation. Long-term incubation triggered a desensitization of PDGFR to its own agonist, with a progressive inhibition of PDGFRbeta phosphorylation, associated with increased formation of HNE-PDGFR adducts in SMC and in vivo, in the aortae of apoE-deficient mice. Hydralazine used as carbonyl scavenger prevented PDGFRbeta inhibition in vitro and in vivo In conclusion, PDGFRbeta is a target for 4-HNE, acrolein and oxidative stress and its progressive inhibition may contribute to defective SMC proliferation and decrease the stability of a vulnerable plaque.
Vindis
Cecile
C
INSERM U-466 and Biochemistry Department, IFR-3 1, CHU Rangueil, Toulouse, France.
Escargueil-Blanc
Isabelle
I
Uchida
Koji
K
Elbaz
Meyer
M
Salvayre
Robert
R
Negre-Salvayre
Anne
A
D000171:Acrolein / Q000633:toxicity; D000447:Aldehydes / Q000633:toxicity; D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism / Q000502:physiology*
D000447:Aldehydes; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D000171:Acrolein; D020797:Receptor, Platelet-Derived Growth Factor beta; C027576:4-hydroxy-2-nonenal