Leukotriene B(4) (LTB(4)), a potent leukocyte
chemoattractant derived from the
5-lipoxygenase metabolism of
arachidonic acid, exerts its action by means of specific
cell surface receptors, denoted BLT(1) and BLT(2). In this study, BLT(1) receptor
proteins were detected in human carotid artery
atherosclerotic plaques, colocalizing with markers for macrophages, endothelial cells, and vascular smooth muscle cells (SMC). Challenge of human coronary artery SMC with either LTB(4) or
U75302, a partial agonist that is selective for the BLT(1) receptor, induced an approximately 4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT(1) receptors. LTB(4) 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 BLT(1) receptor
mRNA compared with medial SMC. BLT receptor up-regulation in the intima in vivo, as well as that induced by IL-1beta in vitro, were prevented by transfection with a dominant-negative form of Ikappa
kinase beta carried by adenovirus, indicating that BLT(1) receptor expression depends on NF-kappaBeta. These results show that LTB(4) activates functional BLT(1) receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT(1) receptors were up-regulated through an Ikappa
kinase beta/
NF-kappaB-dependent pathway. Inhibition of LTB(4)/BLT(1) signaling during the response to
vascular injury reduced intimal
hyperplasia, suggesting this pathway as a possible target for
therapy.