Abstract 5511: Leukotriene B4 Enhances the Activity of NF-κB Pathway through BLT1 and BLT2 Receptors in Atherosclerosis
Leukotriene B4 (LTB4) is a powerful chemoattractant and proinflammatory mediator that is involved in the pathophysiology of atherosclerosis. It works through its membrane receptors BLT1 and BLT2. To assess the mechanisms involved in the proatherogenic effect of LTB4. To study the expression of the 5-Lipoxygenase (5-LO) pathway and LTB4 receptors in blood and plaques from patients with atherosclerosis. In cultured monocytic cells, LTB4 induced phosphorylation of ER1/2, JNK1/2 and AKT (p<0.005 for all; western blot) and also increased NF-κB DNA binding activity (p<0.001; EMSA) via BLT1 and BLT2. Furthermore, LTB4 elicited interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and Tumor Necrosis Factor-α (TNF-α) mRNA overexpression by an NF-κB dependent mechanism via BLT1 and BLT2 (p=0.001 for all; Real Time PCR). Patients with carotid atherosclerosis showed a significant enhancement of 5-LO (p=0.0001), 5-LO activating protein (FLAP) (p=0.02), Leukotriene A4 hydrolase (LTA4H) (p=0.001), BLT1 (p=0.005) and BLT2 (p=0.009) mRNA expression (Real Time PCR) in peripheral blood mononuclear cells and of LTB4 plasma levels (p=0.004; ELISA), as compared to healthy subjects. In these patients, there was overexpression of 5-LO (p=0.001), LTA4-H (p=0.002) and BLT1 (p=0.035) in the shoulder of carotid plaques as compared to the fibrous cap (inmunohistochemistry). In cultured monocytic cells, LTB4 induces the expression of IL-6, MCP-1 and TNF-α via BLT1 and BLT2. Patients with carotid atherosclerosis display an increased expression of the components of 5-LO pathway and of BLT receptors in the shoulder of their plaques, and in blood. The blockade of this pathway could be a therapeutic target in atherothrombosis.