Copper and cell‐oxidized low‐density lipoprotein induces activator protein 1 in fibroblasts, endothelial and smooth muscle cells

Abstract

The effect of cupric ion-or endothelial cell-oxidized low-density lipoproteins (LDL) on transcription factor API activation was investigated by electrophoretic mobility shift assay. Both oxidized LDL induced API activation in fibroblasts, endothelial and smooth muscle cells. This phenomenon was also observed in the presence of cycloheximide. a-Tocopherol, a lipophilic free radical scavenger, and TV-acetylcysteine, an hydrophilic antioxidant, partially inhibited the stimulatory effect of Cu 2+ -oxidized LDL. LDL modified by the mixture of the oxygen radicals OH-and 0 2 -, which generated lipid peroxidation products, also initiated API activation, whereas LDL modified by OH-alone, which did not lead to marked LDL lipid peroxidation, was ineffective. Thus, lipid peroxidation products seem at least partially involved in the activation mechanism. Since API activity is essential for the regulation of genes involved in cell growth and differentiation, our study suggests that the oxidative stress induced by oxidized LDL might be related to the fibroproliferative response observed in the atherosclerotic plaque. © 1997 Federation of European Biochemical Societies.

Dual Roles for Lipolysis and Oxidation in Peroxisome Proliferation-Activator Receptor Responses to Electronegative Low Density Lipoprotein

“…Oxidized LDL, taken up by scavenger receptors (SR), promotes inflammatory responses through NF B and AP-1 activation. Here we demonstrate that whereas LDL(Ϫ) uptake through the LDLR induces VCAM1 expression through activation of NF B and AP-1, LDL(Ϫ) hydrolysis by LPL has the opposite effect, decreasing VCAM1 expression by generating PPAR␣ ligands and suppressing NF B and AP-1 responses (7,38,39). These LPL effects on LDL(Ϫ), which are independent of the LDLR, may be especially relevant given the presence of LDL(Ϫ) in the circulation.…”

Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis

“…49 Except for SRA and CD36, there is no known scavenger receptor contributing to oxLDL uptake in considerable amounts. 50 Furthermore, among the different scavenger receptors, only the CD36 receptor has signal transduction properties 21,23,41,51,52 by which PPAR␥, 41 nuclear factor-B, 21 activator-protein 1, 53 and src-related protein thyrosine kinases 23 seem to be involved. Our data that the CD36 receptor blocking antibody, OKM5, reduced oxLDLstimulated matrix synthesis indicate that binding of oxLDL to CD36 is a prerequisite of oxLDL-stimulated matrix synthesis.…”

Role of Sphingosine 1-Phosphate in the Mitogenesis Induced by Oxidized Low Density Lipoprotein in Smooth Muscle Cells via Activation of Sphingomyelinase, Ceramidase, and Sphingosine Kinase

“…In addition, incubation of SMC with the serpin TPCK which blocked SM hydrolysis was found to abolish the activation of MAPK and mitogenesis (13). Finally, S1P is known to enhance the DNA binding activity of the transcription factor AP-1 (52), a molecular event believed to take place downstream of MAPK, and which has also been described following exposure to oxLDL (53). Therefore, although other potential mechanisms (24) cannot be excluded, the activation of the MAPK pathway represents a likely candidate to transduce the oxLDL-induced mitogenic signaling of S1P.…”