Desensitization of platelet-derived growth factor receptor-β by oxidized lipids in vascular cells and atherosclerotic lesions -: Prevention by Aldehyde!Scavengers

The platelet-derived growth factor receptor-beta (PDGFR beta) 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 PDGFR beta pathway, but the long-term effects of oxLDL on PDGFR beta function are not well understood. We found that oxLDL induced a dual effect on PDGFR beta signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFR beta desensitization was not attributable to PDGFR beta degradation or changes in localization to the caveolae but instead resulted from decreased PDGF binding and inhibition of PDGFR beta tyrosine kinase activity. This inhibition was associated with formation of (4HNE)- and acrolein-PDGFR beta adducts and was mimicked by preincubation of cells with 4HNE. These PDGFR beta 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 PDGFR beta 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.