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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:127.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Activation of Thromboxane Receptor Upregulates Interleukin (IL)-1β–Induced VCAM-1 Expression Through JNK Signaling

Hossein Bayat; Shanqin Xu; David Pimentel; Richard A. Cohen; Bingbing Jiang

From the Whitaker Cardiovascular Institute, Vascular Biology Unit, Department of Medicine, Boston University School of Medicine, Mass.

Correspondence to Bingbing Jiang, PhD, Vascular Biology Unit, X704, 650 Albany Street, Boston, MA 02118. E-mail bjiang{at}bu.edu

Abstract

Objective— Activation of thromboxane receptors (TPr) is implicated in atherosclerosis and inflammation. This study examined how activation of TPr modulates IL-1β–induced vascular cell adhesion molecule (VCAM)-1 expression in aortic vascular smooth muscle cells (VSMCs).

Methods and Results— In VSMCs, activation of TPr with U46619, a stable thromboxane A₂ mimetic, alone did not induce VCAM-1 expression, but enhanced that caused by IL-1β. The enhancement of VCAM-1 expression caused by U46619 occurred at the transcriptional level and was inhibited either by SP600125, a c-Jun N-terminal kinase (JNK) inhibitor, or by overexpression of a dominant-negative JNK1, but not by SB203580, a p38 mitogen-activated protein kinase inhibitor. The activation of JNK by U46619 resulted in enhanced phosphorylation and nuclear translocation of c-Jun associated with an enhanced activation of activator protein (AP)-1, which were abolished by SQ29548, a TPr antagonist, or the JNK inhibitor. Treatment of the cells with U46619 alone did not induce NF-B activation. Furthermore, U46619 enhanced IL-1β–induced THP-1 monocyte binding to VSMCs, which was inhibited by SQ29548 or SP600125.

Conclusion— This study demonstrates that activation of TPr upregulates IL-1β–induced VCAM-1 expression by enhancing the activation of JNK pathway that leads to enhanced AP-1 activation.

Activation of thromboxane receptors (TPr) is implicated in atherosclerosis and inflammation. This study demonstrated that in vascular smooth muscle cells, activation of TPr with U46619 alone does not induce vascular cell adhesion molecule (VCAM)-1 expression, but enhances IL-1β–induced VCAM-1 expression through enhancing JNK-dependent AP-1 activation, which enhances monocyte adhesion.

Key Words: adhesion molecules • cytokines • eicosanoids • receptors • smooth muscle cells