Leukotriene B4 signaling through NF-kappaB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia.
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.
Bäck
Magnus
M
Department of Medicine, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Bu
De-xiu
DX
Bränström
Robert
R
Sheikine
Yuri
Y
Yan
Zhong-Qun
ZQ
Hansson
Göran K
GK
D000578:Amidines / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology; D020212:Carotid Artery Injuries / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D004594:Electrophysiology; D005233:Fatty Alcohols / Q000494:pharmacology; D006018:Glycols / Q000494:pharmacology; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism; D007975:Leukotriene B4 / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018102:Receptors, Leukotriene B4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017539:Tunica Intima / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D000578:Amidines; D002219:Carbamates; D005233:Fatty Alcohols; D006018:Glycols; C513240:LTB4R protein, human; C513241:Ltb4r protein, rat; D016328:NF-kappa B; D058910:Purinergic P2 Receptor Agonists; D058919:Purinergic P2 Receptor Antagonists; D018102:Receptors, Leukotriene B4; D018048:Receptors, Purinergic P2; C062137:U 75302; D007975:Leukotriene B4; C424425:amelubant