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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1414.)
© 2001 American Heart Association, Inc.

Vascular Biology

Adenovirus-Mediated Overexpression of Dominant-Negative Mutant of c-Jun Prevents Intercellular Adhesion Molecule-1 Induction by LDL

A Critical Role for Activator Protein-1 in Endothelial Activation

Nanping Wang; Lynne Verna; Hai-ling Liao; Alex Ballard; Yi Zhu; Michael B. Stemerman

From the Division of Biomedical Sciences, University of California, Riverside.

Correspondence to Nanping Wang, MD, PhD, Division of Biomedical Sciences, University of California, Riverside, CA 92521. E-mail nwang{at}ucrac1.ucr.edu

Abstract—— Low density lipoprotein (LDL) induces intercellular adhesion molecule-1 (ICAM-1) gene expression and leads to endothelial cell (EC) leukocyte adhesion. However, the transcriptional mechanism for LDL-induced EC perturbation remains to be fully explained. Activator protein-1 (AP-1) is induced after the exposure of ECs to LDL. In the present study, a regulated adenovirus expressing a dominant-negative mutant of c-Jun (TAM-67) was used to examine the role of AP-1 in the LDL-induced ICAM-1 activation. Overexpression of TAM-67 specifically inhibited AP-1 activation and prevented the LDL-activated surface expression of ICAM-1 protein in human umbilical vein ECs and human coronary artery ECs. Northern analyses and promoter transactivation assays indicated that this effect of TAM-67 was likely mediated through a suppression of the transcriptional regulation of the ICAM-1 gene. Functionally, TAM-67 attenuated leukocyte adherence to ECs in response to LDL. Furthermore, electrophoresis mobility shift assays and site-directed mutagenesis suggested that an AP-1–like motif in the promoter region of the human ICAM-1 gene was a critical cis element for LDL induction. These results, for the first time, provide evidence suggesting that AP-1 is a major regulatory mechanism leading to endothelial activation.

Key Words: LDL • endothelium • adhesion molecules • transcription factors • gene expression

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