Objective-Based on its role in inflammation and matrix degradation, we hypothesized a role for osteoprotegerin (OPG), RANK, and RANK ligand (RANKL) in coronary artery disease. Methods and Results-We examined the expression of various members of the OPG/RANKL/RANK axis in patients with stable and unstable angina and in the atherosclerotic lesions of apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Our findings were: (1) Serum levels of OPG were raised in patients with unstable angina (nϭ40), but not in those with stable angina (nϭ40), comparing controls (nϭ20); (2) mRNA levels of RANKL were increased in T-cells in unstable angina patients accompanied by increased expression of RANK in monocytes; (3) strong immunostaining of OPG/RANKL/RANK was seen within thrombus material obtained at the site of plaque rupture during acute myocardial infarction; (4) OPG/RANKL/RANK was expressed in the atherosclerotic plaques of apoE Ϫ/Ϫ mice, with RANKL located specifically to the plaques; and (5) Key Words: arteriosclerosis Ⅲ inflammation Ⅲ plaque stability N umerous inflammatory mediators seem to play a pathogenic role in coronary artery disease (CAD), promoting atherogenesis and plaque destabilization, leading to thrombus formation with development of acute coronary syndromes. 1,2 However, although the participation of inflammatory mediators in the atherosclerotic process has become widely recognized, the identification and characterization of the different actors are not fulfilled.Receptor activator of nuclear factor-kB ligand (RANKL), its membrane-bound receptor RANK and its soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor (TNF) receptor superfamily. These factors have been identified as candidate mediators for paracrine signaling in bone metabolism but are also involved in modulation of the immune response through interaction with dendritic cells, T-cell activation, and B-cell maturation. 3,4 The pleiotropic effects of the OPG/RANKL/RANK system, such as modulation of cell survival, mineralization and inflammation, make it an interesting candidate mediator in the progression and destabilization of atherosclerotic lesions. mRNA and protein expression of OPG and RANKL have been detected in atherosclerotic plaques in humans. 5,6 Moreover, raised serum levels of OPG are reported in CAD patients and have also been shown to predict cardiovascular mortality in elderly women. 7-9 Although these findings may suggest the involvement of the OPG/RANKL/RANK system in atherogenesis, our knowledge of the role of this system in human CAD, and particularly in acute coronary syndromes, is still limited.Based on its involvement in inflammation and matrix degradation, we in the present study attempted to further clarify the potential role of the OPG/RANKL/RANK system in atherogenesis and acute coronary syndromes by different approaches including clinical studies in patients with sta-

The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

Adaptive immunity has a major impact on atherosclerosis, with pro- and anti-atherosclerotic effects exerted by different subpopulations of T cells. Transforming growth factor-β (TGF-β) may promote development either of anti-atherosclerotic regulatory T cells or of T helper 17 (TH17) cells, depending on factors in the local milieu. We have addressed the effect on atherosclerosis of enhanced TGF-β signaling in T cells. Bone marrow from mice with a T cell-specific deletion of Smad7, a potent inhibitor of TGF-β signaling, was transplanted into hypercholesterolemic Ldlr(-/-) mice. Smad7-deficient mice had significantly larger atherosclerotic lesions that contained large collagen-rich caps, consistent with a more stable phenotype. The inflammatory cytokine interleukin-6 (IL-6) was expressed in the atherosclerotic aorta, and increased mRNA for IL-17A and the TH17-specific transcription factor RORγt were detected in draining lymph nodes. Treating Smad7-deficient chimeras with neutralizing IL-17A antibodies reversed stable cap formation. IL-17A stimulated collagen production by human vascular smooth muscle cells, and RORγt mRNA correlated positively with collagen type I and α-smooth muscle actin mRNA in a biobank of human atherosclerotic plaques. These data link IL-17A to induction of a stable plaque phenotype, could lead to new plaque-stabilizing therapies, and should prompt an evaluation of cardiovascular events in patients treated with IL-17 receptor blockade.