HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Buy All Versions of this Article: fj.08-120345v1 23/4/1081    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harja, E. Articles by Yan, S.-F. Search for Related Content PubMed PubMed Citation Articles by Harja, E. Articles by Yan, S.-F.

Mice deficient in PKCβ and apolipoprotein E display decreased atherosclerosis

Evis Harja^*,1, Jong Sun Chang^*,1, Yan Lu^*, Michael Leitges, Yu Shan Zou^*, Ann Marie Schmidt^* and Shi-Fang Yan^*,2

^* Division of Surgical Science, Department of Surgery, Columbia University, Medical Center, New York, New York, USA; and

Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway

²Correspondence: Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, BB1705, New York, NY 10032, USA. E-mail: sy18{at}columbia.edu

Endothelial activation is a central initiating event in atheroma formation. Evidence from our laboratory and others has demonstrated links between activation of early growth response-1 (Egr-1) and atherosclerosis and also has demonstrated that activated protein kinase C (PKC) βII is a critical upstream regulator of Egr-1 in response to vascular stress. We tested the role of PKCβ in regulating key events linked to atherosclerosis and show that the aortas of apoE^–/– mice display an age-dependent increase in PKCβII antigen in membranous fractions vs. C57BL/6 animals with a 2-fold increase at age 6 wk and a 4.5-fold increase at age 24 wk. Consistent with important roles for PKCβ in atherosclerosis, a significant decrease in atherosclerotic lesion area was evident in PKCβ^–/–/apoE^–/– vs. apoE^–/– mice by 5-fold, in parallel with significantly reduced vascular transcripts for Egr-1 and matrix metalloproteinase (MMP)-2 antigen and activity vs. apoE^–/– mice. Significant reduction in atherosclerosis of 2-fold was observed in apoE^–/– mice fed ruboxistaurin chow (PKCβ inhibitor) vs. vehicle. In primary murine and human aortic endothelial cells, the PKCβ-JNK mitogen-activated protein kinase pathway importantly contributes to oxLDL-mediated induction of MMP2 expression. Blockade of PKCβ may be beneficial in mitigating endothelial perturbation and atherosclerosis.—Harja, E., Chang, J. S., Lu, Y., Leitges, M., Zou, Y. S., Schmidt, A. M., Yan, S.-F. Mice deficient in PKCβ and apolipoprotein E display decreased atherosclerosis.

Key Words: signal transduction • MMP-2 • JNK • Egr-1