High levels of soluble lectinlike oxidized low-density lipoprotein receptor-1 are associated with carotid plaque inflammation and increased risk of ischemic stroke

Abstract

Background—When the lectinlike oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a scavenger receptor for oxLDL, binds oxLDL, processes leading to endothelial dysfunction and inflammation are promoted. We aimed to study release mechanisms of LOX-1 and how circulating levels of soluble LOX-1 (sLOX-1) relate to plaque inflammation and future risk for ischemic stroke. Methods and Results—Endothelial cells and leukocytes were used to study release of sLOX-1. Plasma levels of sLOX-1 were determined in 4703 participants in the Malmö Diet and Cancer cohort. Incidence of ischemic stroke was monitored. For 202 patients undergoing carotid endarterectomy, levels of sLOX-1 were analyzed in plasma and plaque homogenates and related to plaque inflammation factors. Endothelial cells released sLOX-1 when exposed to oxLDL. A total of 257 subjects experienced stroke during a mean follow-up of 16.5 years. Subjects in the highest tertile of sLOX-1 had a stroke hazard ratio of 1.75 (95% CI, 1.28–2.39) compared with those in the lowest tertile after adjusting for age and sex. The patients undergoing carotid endarterectomy had a significant association between plasma sLOX-1 and the plaque content of sLOX-1 (r=0.209, P=0.004). Plaques with high levels of sLOX-1 had more oxLDL, proinflammatory cytokines, and matrix metalloproteinases. Conclusions—Our findings demonstrate that oxLDL induces the release of sLOX-1 from endothelial cells and that circulating levels of sLOX-1 correlate with carotid plaque inflammation and risk for ischemic stroke. These observations provide clinical support to experimental studies implicating LOX-1 in atherosclerosis and its possible role as target for cardiovascular intervention.