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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1159.)
© 2001 American Heart Association, Inc.

Vascular Biology

LDL-Activated p38 in Endothelial Cells Is Mediated by Ras

Yi Zhu; Hailing Liao; Nanping Wang; Kuo-Sheng Ma; Lynne K. Verna; John Y.-J. Shyy; Shu Chien; Michael B. Stemerman

From the Division of Biomedical Sciences, University of California, Riverside, and the Department of Bioengineering and Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla (S.C.), Calif.

Correspondence to Yi Zhu, MD, Division of Biomedical Sciences, University of California, Riverside, CA 92521. E-mail yi.zhu{at}ucr.edu

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

Key Words: p38 • ATF-2 • Ras • LDL • ECs

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