Lipid oxidation products and oxidized low-density lipoproteins impair platelet-derived growth factor receptor activity in smooth muscle cells: Implication in atherosclerosis

Abstract

The platelet-derived growth factor receptor-beta (PDGFRβ) 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 PDGFRβ signaling. Short-term incubation of SMCs with oxLDLs and 4-HNE induced PDGFRβ activation. Long-term incubation triggered a desensitization of PDGFR to its own agonist, with a progressive inhibition of PDGFRβ 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 PDGFRβ inhibition in vitro and in vivo. In conclusion, PDGFRβ 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. © W. S. Maney & Son Ltd.