Desensitization of Platelet-Derived Growth Factor Receptor-β by Oxidized Lipids in Vascular Cells and Atherosclerotic Lesions

Abstract

Abstract-The platelet-derived growth factor receptor-␤ (PDGFR␤) 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␤ pathway, but the long-term effects of oxLDL on PDGFR␤ function are not well understood. We found that oxLDL induced a dual effect on PDGFR␤ signaling. Initial activation of the PDGFR was followed by desensitization of the receptor. PDGFR␤ desensitization was not attributable to PDGFR␤ degradation or changes in localization to the caveolae but instead resulted from decreased PDGF binding and inhibition of PDGFR␤ tyrosine kinase activity. This inhibition was associated with formation of (4HNE)-and acrolein-PDGFR␤ adducts and was mimicked by preincubation of cells with 4HNE. These PDGFR␤ 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␤ 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. Key Words: atherosclerosis Ⅲ oxidized LDL Ⅲ PDGF receptor Ⅲ cell proliferation Ⅲ signaling D uring atherogenesis, the formation of fibroatheroma plaques involves a complex sequence of events, including endothelial activation, transendothelial migration of mononuclear cells, lipoprotein oxidation, lipid accumulation in macrophagic cells, smooth muscle cell (SMC) migration and proliferation, and local inflammatory response. 1,2 Low-density lipoproteins (LDLs) are atherogenic 3 after undergoing oxidative modifications. 4 Oxidized LDLs (oxLDLs), present in atherosclerotic areas, exert various biological effects potentially involved in atherogenesis, including lipid accumulation in macrophages (foam cells), changes in gene expression of adhesion molecules, cytokines, growth factors and coagulation proteins, cell migration, cell proliferation, apoptosis, and local inflammatory/immune response. 4,5 SMC migration and proliferation play a critical role in the formation of fibrous cap of atherosclerotic plaques, whereas toxic events are potentially involved in endothelial cell injury, necrotic core formation, and plaque rupture. 1,2,6 Excessive SMC proliferation and extracellular matrix biosynthesis may lead to occlusive lesions. 1 In contrast, the "thin cap fibroatheroma" containing inflammatory cells and a lipid-rich core is generally a vulnerable plaque prone to atherothrombotic events. [7][8][9] Proliferation of SMC is regulated by numerous growth factors and cytokines 8,10 and by oxLDL. 11,12 Platelet-derived growth factor (PDGF) plays a major role in the fibroproliferative response during atherogenesis and restenosis. 1,13 PDGF-induced signaling is mediated by PDGF receptor-␣ (PDGFR␣) and PDGFR␤, which belong to the large fa...

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

“…HNE can particularly form adducts with PDGFR (platelet-derived growth factor receptor) in atherosclerotic aortas and the use of the antioxidant hydralazine prevents HNE-related adduction and slows the progression of the disease. 38 HNE could also promote chronic inflammation by stimulating the expression and the synthesis of MCP-1 (monocyte chemotactic protein 1) and TGFb (transforming growth factor b) in macrophages and smooth muscle cells. 39 Moreover, HNE could affect the vascular cells' barrier integrity, leading to apoptosis of endothelial cells.…”

Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

“…Desensitization of platelet derived growth factor receptor beta [27] In vitro and In vivo Inhibition of thioredoxin and thioredoxin reductase [28] Caco-2 human adenocarcinoma cells…”

Suppression of Oxidized LDL-Induced PDGF Receptor .BETA. Activation by Ginkgo Biloba Extract Reduces MMP-1 Production in Coronary Smooth Muscle Cells

“…The activation of ERK1/2 was mediated by the activation of receptors for growth factors such as PDGFR-in SMCs 36,37) . We and other investigators showed that oxLDL stimulated the activation of PDGFR-in hCSMCs and rabbit arterial SMCs 15,38,39) . Our recent study further demonstrated that the production of MMP-1 induced by oxLDL and 4-HNE was suppressed under conditions where the activation of PDGFR-and ERK1/2 was inhibited by an inhibitor of tyrosine kinase (AG1295 and genistein) and by an inhibitor of mitogen-activated protein kinase/ERK kinase (PD98059), respectively 15) .…”

“…ox-LDL and 4-HNE have been shown to induce the activation of PDGFR-in hCSMCs and rabbit arterial SMCs 15,38,39) . We further reported that inhibition of the oxLDL-induced activation of PDGFR-resulted in the suppression of ERK1/2 phosphorylation and MMP-1 production 15) , suggesting that PDGFR-mediates the ERK1/2-dependent production of MMP-1 induced by oxLDL; therefore, the effects of Ginkgolon-24 on the activation of PDGFR-were examined.…”