amelubant and Hyperplasia

The lipid-derived inflammatory mediators leukotrienes (LTs) are produced during vascular injury. The aim of the present study was to determine the role of LT receptor signaling in the pathophysiology of in-stent stenosis.. New Zealand White rabbits were fed 0.3% cholesterol and subjected to angioplasty with balloon dilatation and stent implantation in the right carotid artery. Rabbits treated for 2 weeks with the BLT receptor antagonist BIIL284 (3 mg/kg once daily by oral gavage) displayed a significantly reduced in-stent intimal hyperplasia in carotid arteries compared with vehicle-treated rabbits. In addition, BIIL284 treatment significantly reduced the extracellular matrix metalloproteinase (MMP)-2 and MMP-9 activities in stented arteries. The inhibited MMP-9 activity was correlated with decreased macrophage content in the lesions. The LTB(4)-induced migration of vascular smooth muscle cells was significantly inhibited by transfection with siRNA against MMP-2. Finally, human arteries subjected to ex vivo angioplasty and stent implantation displayed an increased in-stent intimal hyperplasia and higher MMP-2 and -9 activities in the presence of LTB(4).. These results suggest a key role of LT signaling in the extracellular matrix degradation associated with hyperlipidemia and in-stent stenosis. In conclusion, targeting LT receptors may represent a therapeutic strategy in atherosclerosis and interventional cardiology.

Topics: Administration, Oral; Amidines; Angioplasty, Balloon; Animals; Carbamates; Carotid Artery, Common; Carotid Stenosis; Cell Line; Cell Movement; Cell Proliferation; Cholesterol, Dietary; Disease Models, Animal; Extracellular Matrix; Humans; Hyperplasia; Leukotriene Antagonists; Leukotriene B4; Macrophages; Male; Mammary Arteries; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Organ Culture Techniques; Rabbits; RNA Interference; RNA, Small Interfering; Secondary Prevention; Stents; Time Factors; Transfection

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.

Topics: Amidines; Analysis of Variance; Animals; Atherosclerosis; Blotting, Western; Carbamates; Carotid Artery Injuries; Cell Movement; Electrophysiology; Fatty Alcohols; Glycols; Humans; Hyperplasia; Leukotriene B4; Male; Muscle, Smooth, Vascular; NF-kappa B; Patch-Clamp Techniques; Polymerase Chain Reaction; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Leukotriene B4; Receptors, Purinergic P2; Signal Transduction; Tunica Intima; Up-Regulation