Enhanced T-Cell Expression of RANK Ligand in Acute Coronary Syndrome

Abstract

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-

Bovine lactoferrin improves bone mass and microstructure in ovariectomized rats via OPG/RANKL/RANK pathway

“…In bone, RANKL is expressed most abundantly in MSCs, osteoblasts and T cells [29] . Despite OPG being a known inhibitor of RANKL, its biological effect may depend on the molar ratio between RANKL and OPG [30] . In this study of ovariectomized rats, we demonstrated that although LF treatment seems to have an inhibitory effect on RANKL, it enhances OPG.…”

Serum osteoprotegerin concentrations are decreased in women with the polycystic ovary syndrome

“…On one hand, by failing to neutralize RANKL, reduced OPG levels might favor cardiovascular disease, because RANKL overexpression is a prominent feature prone to rupture vulnerable atherosclerotic lesions, RANKL may also contribute to the transition from a stable to an unstable plaque (30), and the serum level of RANKL is a highly significant predictor of cardiovascular disease (31). However, it must be noted that neither serum RANKL levels nor the serum RANKL/OPG molar ratio were different in our PCOS patients compared with the non-hyperandrogenic Figure 1 Serum osteoprotegerin (OPG) and RANKL concentrations, and the serum RANKL/OPG molar ratio, in obese and nonobese PCOS patients (grey boxes) and non-hyperandrogenic controls (white boxes).…”

Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

“…TNFa, OX40/OX40L and RANK/ RANKL) and inhibitory (e.g. TRAIL) effects on this process [6][7][8][9][10][11].…”