Leukotriene B4 signaling through NF-κB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia

Leukotriene B-4 (LTB4) a potent leukocyte chemoattractant derived from the 5-lipoxygenase metabolism of arachidonic acid, exerts its action by means of specific cell surface receptors, denoted BLT1 and BLT2. In this study, BLT1 receptor proteins were detected in human carotid artery atherosclerotic plaques, colocalizing with markers for macrophages, enclothelial cells, and vascular smooth muscle cells (SMC). Challenge of human coronary artery SMC with either LTB4 or U75302, a partial agonist that is selective for the BLT1 receptor, induced an approximate to 4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT1 receptors. LTB4 induced migration and proliferation of SMC in vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg/kg, once daily) for 14 days after carotid artery balloon injury in vivo inhibited intimal hyperplasia in rats. In the latter model, SMC derived from the intima exhibited increased levels of BLT1 receptor mRNA compared with medial SMC. BLT receptor up-regulation in the intima in vivo, as well as that induced by IL-1 beta in vitro, were prevented by transfection with a dominantnegative form of I kappa kinase beta carried by adenovirus, indicating that BLT1 receptor expression depends on NF-kappa B. These results show that LTB4 activates functional BLT1 receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT, receptors were up-regulated through an I kappa kinase P/NF-kappa B-dependent pathway. Inhibition of LTB4/BLT1 signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.