Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 28, Issue 1, Pages 127-134Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.150250
Keywords
adhesion molecules; cytokines; eicosanoids; receptors; smooth muscle cells
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Funding
- NHLBI NIH HHS [P01 HL68758, R01 HL55620] Funding Source: Medline
- NIA NIH HHS [R01 AG27080] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL055620, P01HL068758] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG027080] Funding Source: NIH RePORTER
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Objective-Activation of thromboxane receptors (TPr) is implicated in atherosclerosis and inflammation. This study examined how activation of TPr modulates IL-1 beta-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 A(2) mimetic, alone did not induce VCAM-1 expression, but enhanced that caused by IL-1 beta. 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-kappa B activation. Furthermore, U46619 enhanced IL-1 beta-induced THP-1 monocyte binding to VSMCs, which was inhibited by SQ29548 or SP600125. Conclusion-This study demonstrates that activation of TPr upregulates IL-1 beta-induced VCAM-1 expression by enhancing the activation of JNK pathway that leads to enhanced AP-1 activation.
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