
<ArticleTitle>LDL-activated <prot>p38</prot> in endothelial cells is mediated by <prot>Ras</prot>.</ArticleTitle>
<AbstractText>Endothelial dysfunction is a major atherogenic proinflammatory event. LDL causes the activation and phenotypic changes of cultured vascular endothelial cells (ECs). We previously reported that LDL activates <prot>c-Jun</prot> and <prot>AP-1</prot> in ECs. In this study, we demonstrated that <prot>p38</prot>-<prot>ATF-2</prot> is activated by LDL in human ECs and that this activation is mediated by <prot>Ras</prot>. When ECs are incubated with LDL in pathophysiological concentrations, the <prot>p38</prot>-mediated <prot>ATF-2</prot> phosphorylation and <prot>ATF-2</prot> transactivation are increased in a time- and dose-dependent manner. To elucidate the upstream mechanism in LDL-activated <prot>p38</prot> in ECs, we demonstrate that LDL increases <prot>Ras</prot> translocation from the cytoplasm to the cellular membrane, with concurrent increases in <prot>Ras</prot> binding activity to <prot>GST</prot>-<prot>Raf-1</prot>. Overexpression of RasN17, a dominant negative mutant of <prot>Ras</prot>, attenuates the LDL-induced increases in (1) phosphorylation of <prot>ATF-2</prot>, (2) phosphorylation of <prot>c-Jun</prot>, (3) <prot>AP-1</prot> binding, and (4) <prot>AP-1</prot>-driven luciferase activity. To study the effect of <prot>p38</prot> in the regulation of an LDL targeting gene, we show that a specific <prot>p38</prot> inhibitor attenuates LDL-induced <prot>E-selectin</prot> at the mRNA level. Thus, LDL activates both <prot>p38</prot> and JNK signaling pathways through <prot>Ras</prot> activation, and furthermore, these events may play an important role in LDL-induced endothelial activation.</AbstractText>
