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.