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Cardiovascular Research Advance Access originally published online on October 13, 2008
Cardiovascular Research 2009 81(1):216-225; doi:10.1093/cvr/cvn277
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Leukotriene B4 enhances the activity of nuclear factor-{kappa}B pathway through BLT1 and BLT2 receptors in atherosclerosis

Eva Sánchez-Galán1,2, Almudena Gómez-Hernández1,2, Cristina Vidal1,2, José Luis Martín-Ventura1,2, Luis Miguel Blanco-Colio1,2, Begoña Muñoz-García1, Luis Ortega3, Jesús Egido1,2 and José Tuñón2,4,*

1 Vascular Research Laboratory, Madrid, Spain
2 Autónoma University, Madrid, Spain
3 Department of Pathology, Hospital Clínico, Madrid, Spain
4 Department of Cardiology, Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain

* Corresponding author. Tel: +34 915504816; fax: +34 915497033. E-mail address: j.tunon{at}wanadoo.es

Aims: Leukotriene B4 (LTB4) is a powerful chemoattractant and pro-inflammatory mediator in several inflammatory diseases, including atherosclerosis. It acts through its two membrane receptors, BLT1 and BLT2. The aim of this study was to determine the molecular mechanism involved in the proatherogenic effect of LTB4, BLT1 and BLT2 in atherosclerosis. Moreover, we characterized the expression of 5-lipoxygenase (5-LO) pathway and LTB4 receptors in blood and plaques from patients with carotid atherosclerosis.

Methods and results: In cultured monocytic cells, LTB4 induced a rapid phosphorylation of mitogen-activated protein kinases (MAPKs ERK1/2 and JNK1/2) and PI3K/Akt via BLT1 and BLT2 in a pertussis toxin (PTX)-dependent mechanism (assessed via western blotting) and also increased nuclear factor-{kappa}B (NF-{kappa}B) DNA binding activity (assessed via EMSA) in a MAPK- and reactive oxygen species-dependent mechanism. Furthermore, LTB4 elicited interleukin-6, monocyte chemoattractant protein-1 and tumour necrosis factor-{alpha} mRNA overexpression also via BLT1 and BLT2 by a PTX- and NF-kB-dependent mechanism (assessed by real-time PCR), promoting an inflammatory environment. When compared with healthy subjects, patients with carotid atherosclerosis showed a significant increase in the expression of all the components of the 5-LO pathway and BLT1 and BLT2 mRNA (real-time PCR) in peripheral blood mononuclear cells and LTB4 plasma levels (ELISA). In these patients, an overexpression of 5-LO, leukotriene A-4 hydroxylase (LTA4-H) and BLT1 was noted in the inflammatory region of carotid plaques when compared with the fibrous cap (assessed by immunohistochemistry).

Conclusion: The 5-LO pathway is enhanced in patients with carotid atherosclerosis. Furthermore, its product LTB4 phosphorylates MAPKs and stimulates NF-{kappa}B-dependent inflammation via BLT1 and BLT2 receptors in cultured monocytic cells. The blockade of this pathway could be a novel and potential therapeutic target in atherothrombosis.

KEYWORDS Leukotriene B4; BLT1; BLT2; Inflammation; NF-{kappa}B; Atherosclerosis

Time for primary review: 27 days


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