Association of TRAIL and Its Receptors with Large-Artery Atherosclerotic Stroke.

Xudong Pan,Qianwei Zhong,Aijun Ma,Meng Pang,Kun Wang,Zhang Zhang,Shuna Yang,Pablo Garcia De Frutos

doi:10.1371/journal.pone.0136414

Abstract

ObjectiveTo investigate the association of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, osteoprotegerin (OPG) and death receptor 5 (DR5) with large-artery atherosclerosis (LAA) stroke and its prognosis.MethodsWe included patients with LAA stroke (n = 132) according to the TOAST classification system and controls (n = 60). To evaluate the extent and severity of cerebral atherosclerosis, the LAA stroke group was subdivided into 3 subgroups by number of cerebral arteries with atherosclerotic stenosis (≥50%): single, double and multiple (≥3). Plasma levels of TRAIL, OPG and DR5 were measured by ELISA. Ordinal logistic regression was used to analyze the association between the plasma levels of TRAIL, OPG, DR5 and the severity of cerebral atherosclerosis. Prognosis was determined by the Modified Rankin Scale at 3 months after stroke. Receiver operating characteristic (ROC) curve was used to evaluated TRAIL as a predictor of prognosis.ResultsPlasma TRAIL level was significantly lower for LAA patients than controls (P<0.001), while plasma OPG and DR5 levels were higher (both P<0.001). Logistic regression analysis revealed that risk of severe cerebral atherosclerosis was reduced significantly with increased plasma level of TRAIL (OR 0.438; 95% CI 0.282–0.681; P<0.001), whereas increased with high plasma levels of OPG and DR5 (OR 2.707; 95% CI 1.702–4.302, P <0.001; OR 3.593; 95% CI 1.878–6.869, P <0.001). Plasma TRAIL level was negatively correlated with the prognosis (r = - 0.372, P <0.001). The optimal cut-off value of TRAIL for prognosis was 848.63 pg/mL. The sensitivity and specificity at this cut-off value were 63.1% and 86.2%, respectively. After adding the plasma TRAIL level into the multivariate model of ROC, the area under the ROC curve was increased from 0.639 to 0.785, but the change was not statistical significant (P = 0.146).ConclusionsTRAIL and its receptors OPG and DR5 may be involved in LAA stroke and the plasma level of TRAIL may be a biomarker predicting the severity of cerebral atherosclerosis and the prognosis of LAA stroke.

Highlights

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF ligand super family, which was first discovered and successfully cloned by Wiley et al [1] in 1995
Logistic regression analysis revealed that risk of severe cerebral atherosclerosis was reduced significantly with increased plasma level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), whereas increased with high plasma levels of OPG and death receptor 5 (DR5)
TRAIL and its receptors OPG and DR5 may be involved in Large-artery atherosclerosis (LAA) stroke and the plasma level of TRAIL may be a biomarker predicting the severity of cerebral atherosclerosis and the prognosis of LAA stroke

Summary

Introduction

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF ligand super family, which was first discovered and successfully cloned by Wiley et al [1] in 1995. As a death receptor for TRAIL, death receptor 5 (DR5), cloned by Pan et al [2] in 1997, triggers TRAIL-induced apoptosis after binding to TRAIL. Osteoprotegerin (OPG), as a decoy receptor for TRAIL, blocks TRAIL-induced apoptosis by inhibiting TRAIL binding to the death receptor [3]. Some studies have explored the roles of plasma levels of TRAIL and its receptors in atherosclerosis [7,8,9]. Studies on TRAIL and its receptors (DR5, OPG) in cerebrovascular atherosclerosis are relatively few. The aims of present study were mainly to investigate the association of plasma levels of TRAIL and its receptors with LAA stroke, and explore the relationship between plasma TRAIL and prognosis of LAA stroke as well

Methods

Results

Conclusion