Leukotriene B4signaling through NF-κB-dependent BLT1receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia

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Abstract
Leukotriene B4(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 BLT1and BLT2. In this study, BLT1receptor 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 LTB4or U75302, a partial agonist that is selective for the BLT1receptor, induced an ≈4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT1receptors. LTB4induced migration and proliferation of SMCin vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg/kg, once daily) for 14 days after carotid artery balloon injuryin vivoinhibited intimal hyperplasia in rats. In the latter model, SMC derived from the intima exhibited increased levels of BLT1receptor mRNA compared with medial SMC. BLT receptor up-regulation in the intimain vivo, as well as that induced by IL-1βin vitro, were prevented by transfection with a dominant-negative form of Iκ kinase β carried by adenovirus, indicating that BLT1receptor expression depends on NF-κΒ. These results show that LTB4activates functional BLT1receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT1receptors were up-regulated through an Iκ kinase β/NF-κB-dependent pathway. Inhibition of LTB4/BLT1signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.