Receptor Activator of Nuclear Factor κB Ligand Is a Novel Inducer of Tissue Factor in Macrophages

Abstract

Rationale: Although recent studies have suggested a role for the receptor activator of nuclear factor B ligand (RANKL) in the late stages of atherosclerosis (eg, plaque destabilization and rupture), the underlying mechanisms and subsequent events are unclear.Objective: Because blood clotting is common after plaque rupture, we hypothesized that RANKL influenced tissue factor (TF) expression and activity to initiate the coagulation cascade. Key Words: receptor activator of nuclear factor-B ligand Ⅲ tissue factor Ⅲ thrombosis Ⅲ atherosclerosis A therosclerosis is a well-studied chronic inflammatory disease that is characterized by thickening of the artery walls and formation of atherosclerotic plaques. 1 The later stage of atherosclerosis is accompanied by plaque destabilization and thrombus formation. 2 It is widely accepted that an abundance of active tissue factor (TF) in atherosclerotic plaques is a disastrous factor toward initiation and progression of atherothrombosis. 3,4 Hence, finding TF regulators seems to be of importance to advanced atherosclerosis and acute coronary syndrome. Methods and ResultsThe receptor activator of nuclear factor B ligand (RANKL) was initially identified as a regulator of bone remodeling. Recently, the physiological and pathological relevance of RANKL was extended to vascular biology, including atherosclerosis. 5 RANKL exists in either a cell-bound or a secreted form and it is produced by vascular cells and activated immune cells close to blood vessels. 6 RANKL is upregulated by inflammatory cytokines such as tumor necrosis factor-␣, interleukin-1␣, and interleukin-6. 3 The mRNA level of RANKL was increased in T cells in patients with unstable angina 7 and strong immunoreactivity of RANKL was detected in vulnerable plaques and thrombus from ruptured coronary lesions. 5 Several lines of evidence suggest that RANKL, its receptor (RANK) and osteoprotegerin are involved in atherosclerotic lesion progression and plaque destabilization and calcification. 7,8 We have also previously demonstrated additional vascular roles of RANKL in stimulating angiogenesis, expression of inflammatory adhesion molecules, and endothelial permeability. 9,10 Although RANKL has been emerging as a risk marker for cardiovascular disease, 11 the epidemiological data are still limited to ascertain clear association between RANKL level and cardiovascular disease. 6 Nevertheless, RANKL appears to be correlated with plaque destabilization and thrombosis based on its role in vascular calcium deposition and its prominent expression in advanced lesions. 5,7 In this study, we provide evidence for novel function of RANKL as a potential risk factor for atherothrombosis, demonstrating that RANKL significantly increases TF expression in macrophages, the major cellular component of atherosclerotic plaques.

TWEAK/Fn14 Axis: A Promising Target for the Treatment of Cardiovascular Diseases

“…For example, RANKL induces MCP-1 expression and secretion and matrix MMP activity in SMCs (122). In addition, RANKL induces TF expression in macrophages mainly through the cooperative action of NF-κB, AP-1, and Egr-1, supporting a role of RANKL in the thrombogenicity of atherosclerotic plaques (123). Furthermore, RANK, RANKL, and the decoy receptor for RANKL osteoprotegerin (OPG) have been related with vascular calcification, a crucial step for plaque destabilization and rupture.…”

An osteoclastogenesis system, the RANKL/RANK signalling pathway, contributes to aggravated allergic inflammation

“…Previous studies have shown that RANKL induces the secretion of proinflammatory cytokines through the activation of the p38 MAPK, JNK, ERK, and NF-κB pathways (Kim et al, 2010;Riegel et al, 2012;Seshasayee et al, 2004). Moreover, PI3K activates intracellular calcium levels, and its blocking by Wortmannin inhibits antigen-mediated mast cell degranulation and cytokine production in both rodent and human mast cells (Okayama et al, 2003).…”

Update on the Pathophysiological Role of Intracellular Signaling Pathways in Atherosclerotic Plaques and Ischemic Myocardium

“…Importantly, pre-incubation with statins has been shown to reduce ERK 1/2 phosphorylation and associated pro-inflammatory functions in response to C-reactive protein (CRP) in human monocytes [51]. Confirming the pro-inflammatory relevance of ERK activation, recent findings also indicate that ERK1/2 pathway is crucial for pro-thrombotic in vitro activities of receptor activator of nuclear factor κB ligand (RANKL) in macrophages [52]. Accordingly, we recently showed that that ERK1/2 activation is pivotal for the neutrophilic release of matrix metalloproteases (MMPs) in response to RANKL [53].…”