No abstract

Background— Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis. Methods and Results— This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E–deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8 + cells, and expression of the murine major histocompatibility complex class II molecule I-A b increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines. Conclusions— Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

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 BLT1 and BLT2. In this study, BLT1 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 BLT1 receptor, induced an Ϸ4-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 mg͞kg, 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-1␤ in vitro, were prevented by transfection with a dominantnegative form of I kinase ␤ carried by adenovirus, indicating that BLT1 receptor expression depends on NF-〉. These results show that LTB4 activates functional BLT1 receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT1 receptors were up-regulated through an I kinase ␤͞NF-B-dependent pathway. Inhibition of LTB4͞BLT1 signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.restenosis ͉ cell proliferation ͉ chemotaxis ͉ lipoxygenase ͉ eicosanoids L eukotrienes (LTs) are inflammatory mediators that are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism (1). Leukotrienes exert their actions by means of membrane-bound G protein-coupled receptors; CysLT receptors, which are activated by leukotrienes C 4 , D 4 , and E 4 ; and BLT receptors, which are activated by leukotriene B 4 (LTB 4 ) (2, 3). The last class consists of two receptor subtypes, BLT 1 and BLT 2 , representing the high-and low-affinity receptors for LTB 4 , respectively (4, 5). BLT receptors are expressed on leukocytes; neutrophils, eosinophils, and T lymphocytes all migrate in response to LTB 4 (6, 8-11).A major role for the leukotriene pathway in vascular disease was suggested by studies of a congenic mouse strain demonstrating resistance to atherosclerosis linked to a locus on chromosome 6, within which the gene for 5-LO was mapped subsequently (12). Also, expression of the enzymes and receptors of the 5-LO pathway has been demonstrated in human atherosclerotic plaques (13), and genetic studies have revealed that polymorphism in the 5-LO promoter is associated with an increased carotid artery intima thickness (14) and that the gene encoding the 5-LO-activating protein (FLAP) is associated with an increased risk of stroke and myocardial infarction (15).Although the...