TRAIL-Deficiency Accelerates Vascular Calcification in Atherosclerosis via Modulation of RANKL

Abstract

The osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) cytokine system, not only controls bone homeostasis, but has been implicated in regulating vascular calcification. TNF–related apoptosis-inducing ligand (TRAIL) is a second ligand for OPG, and although its effect in vascular calcification in vitro is controversial, its role in vivo is not yet established. This study aimed to investigate the role of TRAIL in vascular calcification in vitro using vascular smooth muscle cells (VSMCs) isolated from TRAIL−/− and wild-type mice, as well as in vivo, in advanced atherosclerotic lesions of TRAIL−/−ApoE−/− mice. The involvement of OPG and RANKL in this process was also examined. TRAIL dose-dependently inhibited calcium-induced calcification of human VSMCs, while TRAIL−/− VSMCs demonstrated accelerated calcification induced by multiple concentrations of calcium compared to wild-type cells. Consistent with this, RANKL mRNA was significantly elevated with 24 h calcium treatment, while OPG and TRAIL expression in human VSMCs was inhibited. Brachiocephalic arteries from TRAIL−/−ApoE−/− and ApoE−/− mice fed a high fat diet for 12 w demonstrated increased chondrocyte-like cells in atherosclerotic plaque, as well as increased aortic collagen II mRNA expression in TRAIL−/−ApoE−/− mice, with significant increases in calcification observed at 20 w. TRAIL−/−ApoE−/− aortas also had significantly elevated RANKL, BMP-2, IL-1β, and PPAR-γ expression at 12 w. Our data provides the first evidence that TRAIL deficiency results in accelerated cartilaginous metaplasia and calcification in atherosclerosis, and that TRAIL plays an important role in the regulation of RANKL and inflammatory markers mediating bone turn over in the vasculature.

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

“…Circulating TRAIL levels are reduced in patients with acute coronary syndromes, coronary artery disease, diabetes, and myocardial infarction (Michowitz et al, 2005; Schoppet et al, 2006; Volpato et al, 2011; Bisgin et al, 2012). The protective nature of TRAIL is further supported in rodent models of atherosclerosis (Secchiero et al, 2006; Di Bartolo et al, 2011; Di Bartolo et al, 2013), pulmonary hypertension (Hameed et al, 2012) and diabetes (Di Bartolo et al, 2011). TRAIL-mediated anti-apoptotic effects on endothelial cells have been seen (Secchiero et al, 2004; Kavurma & Bennett, 2008; Kavurma et al, 2008).…”

“…A similar effect of TRAIL on VSMCs has been reported in vivo, where vascular injury in Trail − / − mice results in reduced proliferation of VSMCs and intimal thickening (Chan et al, 2010). Interestingly, atherosclerotic plaque development is accelerated in Trail − / − ApoE − / − mice (Di Bartolo et al, 2011; Di Bartolo et al, 2013; Cartland et al, 2014). The atherosclerotic plaques in the Trail − / − ApoE − / − mice have reduced VSMC and collagen content, large necrotic cores, thin fibrous caps, and significantly increased macrophage accumulation in the vulnerable regions of the plaque (Di Bartolo et al, 2011).…”

The effect of bariatric surgery on serum TRAIL and osteoprotegerin levels in obesity complicated by glucose disorders

“…Low TRAIL levels have been associated with adverse events after acute myocardial infarction [13] and greater mortality risk in the general population [14] and in renal failure [15]. This potential role of circulating TRAIL as a marker of longevity, is also reflected in models of TRAIL-deficiency in cardiovascular diseases, diabetes and nephropathy [6,16,17].…”

Autosomal Dominant Polycystic Disease is Associated with Depressed Levels of Soluble Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

“…Accumulating experimental and clinical evidence suggests that TRAIL is associated with atherosclerosis. The circulating TRAIL level is positively associated with endothelial function, and TRAIL deficiency results in accelerated calcification in atherosclerosis (28)(29)(30).…”