Detection of Soluble Lectin-Like Oxidized Receptor (sLOX-1) as a Biomarker To Predict Sickle Cell Disease Vasculopathy
Mingyi Chen, Xin Lin, Hannah Archibald, Ralph Green. UC Davis Medical Center, Sacramento, CA
Background: Sickle cell disease (SCD) crisis is associated with significant morbidity and mortality due to vascular occlusion. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is identified as a major endothelial receptor for oxidized low-density lipoprotein (ox-LDL) as well as aged erythrocytes. Enhanced expression of LOX-1 is implicated in atherosclerosis, inflammation and diabetic vasculopathy. The pathogenesis of SCD vasculopathy mechanistically resembles atherosclerosis. The purpose of this study is to investigate the role of LOX-1 as a biomarker to predict SCD vasculopathy.
Design: We analyzed LOX-1 gene expression by qPCR in human coronary endothelial cells following static incubation with sickle RBCs. We studied in vivo LOX-1 expression in autopsy SCD patient's vasculatures by immunohistochemistry. We measured circulating soluble LOX-1 (sLOX-1) concentrations by sandwich ELISA in the plasma of SCD patients under sickle cell crisis compared with steady-state.
Results: LOX-1 mediated binding and internalization of sickle RBCs in endothelial cells was inhibited by pre-incubation with Ox-LDL.
LOX-1 gene expression in human endothelial cells was significantly increased by incubation with sickle RBCs. Upregulation was detected after 1 hour of incubation, and reached a peak after 6 hours. We studied 48 SCD (Hb SS) patients (26 female, 22 male); vs 17 healthy (Hb AA) control subjects (12 female, 5 male). The SCD cohort comprised pediatric and adult patients in steady-state (33 patients) and vaso-occlusive crisis (VOC; 15 patients). The concentration of circulating sLOX-1 protein in plasma of sickle cell disease patients (mean: 3.09±2.51 ng/mL; range 0.3 – 11.3 ng/mL) was significantly higher (p=0.006) than in control healthy subjects (mean: 1.27±0.79 ng/mL). In 15 SCD patients in VOC, the sLOX-1 concentrations were elevated (mean: 3.70±2.33 ng/mL).
Conclusions: We demonstrate that SCD erythrocytes can induce endothelial LOX-1 expression, and the circulating sLOX-1 levels are elevated in SCD patients in sickle cell crisis. Studies of sLOX-1 in SCD may provide new insights into risk stratification, and may lead to novel therapeutic strategies for sickle cell patients with acute vascular complications.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 47, Wednesday Morning