Soluble Lectin-like Oxidized Low-density Lipoprotein Receptor-1 Research Articles

Associations of Tissue and Soluble LOX-1 with Human Abdominal Aortic Aneurysm.

Background Indication for prophylactic surgical abdominal aortic aneurysm (AAA) repair depends on the maximal aortic diameter. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for uptake of oxidized low-density lipoprotein cholesterol and is implicated in atherosclerosis. A soluble form of LOX-1 (sLOX-1) has been discussed as a novel biomarker in coronary artery disease and stroke. Herein, we assessed the regulation of aortic LOX-1 as well as the diagnostic and risk stratification potential of sLOX-1 in patients with AAA. Methods and Results Serum sLOX-1 was assessed in a case-control study in AAA (n=104) and peripheral artery disease (n=104). sLOX-1 was not statistically different between AAA and peripheral artery disease but was higher in AAA (β=1.28, P=0.04) after adjusting for age, atherosclerosis, type 2 diabetes, prescription of statins, β-blockers, ACE inhibitors, and therapeutic anticoagulation. sLOX-1 was not associated with the aortic diameter, AAA volume, or the thickness of the intraluminal thrombus. Aortic LOX-1 mRNA expression tended to be higher in AAA when compared with disease, and expression was positively associated with cleaved caspase-3, smooth muscle actin, collagen, and macrophage content. Conclusions In AAA, sLOX-1 was differently affected by age, cardiometabolic diseases, and corresponding medical therapies. Comparison with nonatherosclerotic disease would be beneficial to further elucidate the diagnostic potential of sLOX-1, although it was not useful for risk stratification. Aneurysmal LOX-1 mRNA expression was increased and positively associated with smooth muscle cells and collagen content, suggesting that LOX-1 is eventually not deleterious in human AAA and could counteract AAA rupture.

Evaluation of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) and sLOX-1/oxidized LDL ratio as novel biomarkers of acute coronary syndrome.

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the pathophysiology of atherosclerosis and acute coronary syndromes (ACS). In patients with acute coronary syndrome, circulating soluble LOX-1 (sLOX-1) levels are dramatically elevated. This study aimed to assess sLOX-1 levels in acute coronary syndromes and determine the ratio of sLOX-1 and oxidative LDL in cases of myocardial infarction and unstable angina pectoris and the ROC curve for this ratio sLOX-1. A case-control study was conducted at the department of chemistry and biochemistry, college of medicine, Al- Nahrain University, Baghdad, Iraq, from September 2020 to January 2021. In a total of 90 subjects (30 patients with myocardial infarction within the first six hours of chest pains, 30 patients with unstable angina pectoris, and 30 healthy donors). The ELISA technique measured concentrations of sLOX-1 and oxidized LDL. In addition, Troponin and highly sensitive C reactive protein were measured by the same technique (Fluorescence immune assay), and lipid profile was measured using the Spectrophotometer technique. The median level of sLOX-1 in MI group was 476.17 pg/ml (90.88-675.4 pg/ml) which was significantly higher than that of UA patients (median=289.1 pg/ml [62.74-585.43 pg/ml]) and controls (median=144.52 pg/ml [79.17-283.83 pg/ml]) with highly significant differences and the median sLOX-1/OX-LDL ratio in patients with MI was 64.6 (range 15.17-100.15) which was significantly higher than either patients with UA (median=37.6 [7.06-88.65]) or controls (median=25.29 [12.7-43.04]). There were elevated levels of sLOX-1 in acute coronary syndromes. The sLOX-1/oxidized LDL ratio also strongly indicated the diagnosis and a discriminatory force on the ROC curve for myocardial infarction.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS). Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031). Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD. NCT01000701.

High plasma levels of soluble LOX-1 portends poor survival in acute coronary syndromes beyond GRACE 2.0: a multicentre prospective cohort study

Abstract Background While inflammatory states and dyslipidemias confer a dismal prognosis following myocardial ischaemia, the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) which sits at the confluence of these conditions remains elusive. Given soluble LOX-1' (sLOX-1) pivotal role in inflammatory processes underlying atherosclerotic plaque progression, we sought to study its prognostic utility on the risk of adverse events in acute coronary syndromes (ACS). Purpose Hence, we aimed to investigate whether sLOX-1 is an independent predictor of all-cause death at one year beyond traditional and emerging risk factors for poor survival following ACS. Methods 2678 ACS patients were recruited in the prospective, multicentre SPUM-ACS trial, of which 2525 completed follow-up at one year. Major adverse cardiovascular events, including death from any cause, were adjudicated by an independent clinical endpoint committee. By employing high-sensitive enzyme-linked immunosorbent assay, sLOX-1 was assessed in the plasma at the time of presentation in ACS and age-matched chronic coronary syndrome (CCS) patients. Kaplan-Meier survival analysis and Cox proportional hazard regression models, adjusted for baseline variables and the GRACE 2.0 score, were used to study the predictive utility of sLOX-1. Results At the time of presentation, ACS patients, specifically those with ST-segment elevation ACS, had significantly elevated sLOX-1 levels as compared to patients with CCS (median, 35.40 vs. 2.00 pg/ml, P&amp;lt;0.0001). Patients in the upper sLOX-1 tertile were at heightened risk for both death from any cause (crude HR 1.785, 95% CI 1.083–2.941, P&amp;lt;0.05; adjusted HR 2.035, 95% CI 1.176–3.519, P&amp;lt;0.05) and CV death (crude HR 2.447, 95% CI 1.285–4.663, P&amp;lt;0.01; adjusted HR 2.383, 95% CI 1.206–4.710, P&amp;lt;0.05) compared to those in the first tertile. Importantly, sLOX-1 remained an independent predictor of all-cause death after adjustment for known risk factors of adverse outcome and the GRACE 2.0 score (adjusted + GRACE 2.0 HR 1.896, 95% CI 1.034–3.476, P&amp;lt;0.05). Conclusions Plasma sLOX-1 is elevated in ACS patients and predicts poor survival independent of both traditional and emerging risk factors and provides prognostic information beyond GRACE 2.0. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swiss National Science FoundationFoundation for Cardiovascular Research - Zurich Heart House

Soluble LOX-1 and its interplay with hs-CRP predict poor cardiovascular survival in acute coronary syndromes: A multicentre prospective cohort study

Background and Aims: While inflammatory states and dyslipidemia confer a dismal prognosis following myocardial ischaemia, the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) which sits at the interface of these conditions remains elusive. Given the pivotal role of soluble LOX-1 (sLOX-1) in inflammatory processes underlying atherosclerotic plaque progression, we sought to investigate its prognostic utility and interplay with hs-CRP on the risk of adverse cardiovascular events in acute coronary syndromes (ACS).

Association between impaired cutaneous microvascular endothelial function and lectin-like oxidized low-density lipoprotein receptor-1 in patients with coronary slow flow

ObjectiveAlthough increasing studies indicate coronary slow flow (CSF) is a systemic microvascular disorder, whether there is impaired cutaneous microvascular endothelial function in CSF patients remains unclear. This study was designed to test the hypothesis that the cutaneous microvascular endothelial function of CSF patients is impaired and correlates with lectin-like oxidized low-density lipoprotein receptor-1(LOX-1). Methods39 patients with CSF and 45 controls with normal coronary flow were enrolled. Velocity of coronary flow was quantitatively identified by thrombolysis in myocardial infarction frame count (TFC) method. LSCI system was used to assess subjects' cutaneous blood flow at rest and during PORH. Serum soluble LOX-1(sLOX-1) level was measured in all study subjects. ResultsPORH-induced vasodilation was significantly reduced in CSF group in comparison with control group (0.26 ± 0.10 vs 0.35 ± 0.07 APU/mmHg, P < 0.001) and negatively correlated with the mean TFC for three coronary arteries (r = −0.385, P = 0.016). Serum sLOX-1 level in CSF group was significantly increased (582.93 ± 74.89 vs 483.64 ± 51.38 pg/ml, P < 0.001) and positively correlated with mean TFC(r = 0.467, P = 0.003).PORH response amplitudes had a significantly negative relationship with serum sLOX-1 level in CSF patients (r = −0.588, P < 0.001). ConclusionThese data suggest that cutaneous microvascular endothelial function is impaired in patients with CSF, which is closely associated with increased LOX-1 expression.

Association Between Soluble Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 and Coronary Artery Disease in Psoriasis

Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis. To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time. In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year. Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay. Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status. Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P < .001), and were associated with Psoriasis Area Severity Index (PASI) score (β = 0.23; 95% CI, 0.082-0.374; P = .003). Moreover, sLOX-1 was associated with NCB independent of hyperlipidemia status (β = 0.11; 95% CI, 0.016-0.200; P = .023), an association which persisted after adjusting for traditional cardiovascular risk factors, statin use, and biologic psoriasis treatment (β = 0.10; 95% CI, 0.014-0.193; P = .03). At 1 year, in those who had clinical improvement in PASI (eg, >50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (β = 0.14; 95% CI, 0.028-0.246; P = .02). Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.

Evaluation of serum level of soluble lectin-like oxidized low-density lipoprotein receptor-1 and its relationship with severity of preeclampsia and birth weight

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the pattern recognition receptors that plays a critical role in vascular diseases and host immune response, LOX-1 can induce endothelial dysfunction through pathways implicated with oxidative stress and inflammation that ends with vascular lesions. Objective: The objective of the study is to evaluate the serum level of soluble LOX-1 (sLOX-1) in preeclampsia (PE) and normal pregnancy to study its relationship with the severity of PE and birth weight. Materials and Methods: A total of 56 patients with PE were allocated to the study together with 28 healthy pregnant women as normal controls. PE patients divided into 28 mild and 28 severe PE. Levels of serum sLOX-1 were measured by sandwich enzyme-linked immunosorbent assay technique. Results: Results showed a significant increase in the serum sLOX-1 in preeclamptic patients (P

Higher serum lectin-like oxidized low-density lipoprotein receptor-1 in patients with stable coronary artery disease is associated with major adverse cardiovascular events: A multicentre pilot study.

IntroductionLectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in the pathophysiology of atherosclerosis and acute coronary syndromes (ACS). Circulating soluble LOX-1 (sLOX-1) has been linked to the risk of coronary artery disease (CAD). Our aim was to test if baseline serum sLOX-1 was associated with major adverse cardiovascular events (MACE) in patients with stable CAD.Materials and methodsThis multicentre pilot study enrolled 833 stable CAD patients. All patients were followed for two years. Serum sLOX-1 concentrations were detected by enzyme-linked immunosorbent assay (ELISA). The association between sLOX-1 concentrations and MACE was assessed by logistic regression, Kaplan-Meier survival curves and Cox proportional hazards analyses. Logistic regression analysis was employed to assess the predictors of complex lesion.ResultsMultivariate logistic regression analysis revealed that sLOX-1 concentration was an independent predictor of MACE (OR 2.07, 95%CI 1.52 - 2.82; P < 0.001). Kaplan-Meier cumulative survival curves showed that the incidence of MACE in patients with a high sLOX-1 concentration was significantly higher than in patients with an intermediate or low sLOX-1 concentration (P < 0.001). Soluble LOX-1 concentrations were independently correlated with coronary complex lesions (OR 2.32, 95%CI 1.81 - 2.97; P < 0.001).ConclusionsBaseline sLOX-1 concentrations were correlated with 2-year MACE in stable CAD patients. Furthermore, patients with high serum sLOX-1 concentrations had higher cumulative incidence of MACE compared to those with low serum sLOX-1 concentrations.

Serum sLOX-1 Levels Are Correlated with the Presence and Severity of Obstructive Sleep Apnea.

Inflammation plays a critical role in the development and progression of obstructive sleep apnea (OSA). Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) activation is involved in the pathophysiology of inflammatory process-related disorders. This study aims to investigate whether serum soluble LOX-1 (sLOX-1) levels are associated with the presence and severity of OSA. A total of 137 OSA patients and 78 controls were recruited in this study. Serum sLOX-1 levels were measured by enzyme-linked immunosorbent assay. The severity of OSA was assessed by the apnea-hypopnea index (AHI). OSA patients had significantly higher serum sLOX-1 levels compared with controls. Serum sLOX-1 levels elevated with the increment of OSA severity. sLOX-1 was the independent predictor of OSA. Serum sLOX-1 levels were significantly correlated with AHI and high-sensitivity C-reactive protein levels. Serum sLOX-1 levels were independently correlated with the presence and severity of OSA. These findings revealed that sLOX-1 might function as a potential biomarker for monitoring the development and progression of OSA.

Association between plasma sLOX-1 concentration and arterial stiffness in middle-aged and older individuals.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in vascular endothelial function. Vascular endothelial function is a potent regulator of arterial stiffness, an independent risk factor for cardiovascular disease. However, it is unknown whether LOX-1 is associated with arterial stiffness. Plasma concentrations of soluble LOX-1 (sLOX-1) and brachial-ankle pulse wave velocity (baPWV, an index of arterial stiffness) were measured in 143 individuals between 51 and 83 years of age. Plasma sLOX-1 concentration was correlated with baPWV (r = 0.288, p = 0.0005). In stepwise regression analysis, plasma sLOX-1 concentration was associated with baPWV, after adjusting for age; body mass index; blood pressure; heart rate; blood levels of cholesterol, triglycerides, glucose, hemoglobin A1c, and insulin; sex; and use of antihypertensives, lipid-lowering agents, and other medications (R2 = 0.575, p<0.0001). Multiple logistic regression demonstrated that plasma sLOX-1 concentration was independently associated with elevated baPWV (≥14.0 m/s; odds ratio, 1.01; 95% confidence interval, 1.00–1.03; p = 0.03). These results suggest that LOX-1 is associated with arterial stiffness.

Significance of soluble lectin-like oxidized LDL receptor-1 levels in systemic and coronary circulation in acute coronary syndrome.

Background. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) level is a novel biomarker for diagnosis of acute coronary syndrome (ACS); however, this level in the coronary circulation has yet to be examined. Methods. Twenty-seven consecutive patients with ACS and 40 patients with effort angina pectoris (EAP) undergoing percutaneous coronary intervention (PCI) had levels of soluble LOX-1 and LOX-1 index measured in paired blood samples from aorta (Ao) and coronary sinus (CS) just prior to the PCI. Results. We found positive correlations between soluble LOX-1 levels in the Ao and CS in both ACS and EAP patients (P < 0.01, for both). The soluble LOX-1 levels in the Ao and CS were higher in ACS than in EAP patients (P < 0.01, for both). The levels of soluble LOX-1 and LOX-1 index of the CS were significantly greater than those of the Ao in both ACS and EAP patients (P < 0.01, for both). Receiver operating characteristic curves for ACS detection demonstrated high sensitivity and specificity for the soluble LOX-1 and LOX-1 index with no differences between the Ao and CS. Conclusions. The present study showed that circulating soluble LOX-1 originates from coronary circulation and soluble LOX-1 and LOX-1 index are useful biomarkers for ACS.

Simulative and experimental investigation on the cleavage site that generates the soluble human LOX-1

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that mediates the recognition, the binding and internalization of ox-LDL. A truncated soluble form of LOX-1 (sLOX-1) has been identified that, at elevated levels, has been associated to acute coronary syndrome. Human sLOX-1 is the extracellular part of membrane LOX-1 which is cleaved in the NECK domain with a mechanism that has not yet been identified. Purification of human sLOX-1 has been carried out to experimentally identify the cleavage site region within the NECK domain. Molecular modelling and classical molecular dynamics simulation techniques have been used to characterize the structural and dynamical properties of the LOX-1 NECK domain in the presence and absence of the CTLD recognition region, taking into account the obtained proteolysis results. The simulative data indicate that the NECK domain is stabilized by the coiled-coil heptad repeat motif along the simulations, shows a definite flexibility pattern and is characterized by specific electrostatic potentials. The detection of a mobile inter-helix space suggests an explanation for the in vivo susceptibility of the NECK domain to the proteolytic cleavage, validating the assumption that the NECK domain sequence is composed of a coiled-coil motif destabilized in specific regions of functional significance.

Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Plays an Important Role in Vascular Inflammation in Current Smokers

Smoking induces vascular inflammation and increases the risk of cardiovascular events. Lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that is induced by oxidative stress and is associated with atherosclerotic plaque formation and destabilization. LOX-1 interacts with C-reactive protein (CRP) and plays an important role in inflammatory diseases. We therefore hypothesized that LOX-1 may be involved in the onset of smoking-induced vascular inflammation. We measured the soluble LOX-1 (sLOX-1) levels in sera obtained from 207 current smokers. The serum sLOX-1 levels positively correlated with various smoking variables, such as the number of cigarettes smoked per day (r= 0.150, p<0.05), the expired air carbon monoxide (CO) concentrations (r= 0.198, p<0.005) and the Fagerstrom test for nicotine dependence scores (r= 0.190, p<0.01). The serum levels of sLOX-1 also correlated with those of a representative inflammatory marker, the serum high-sensitivity CRP level (hsCRP; r= 0.232, p<0.005). A multivariate regression analysis revealed the independent determinants of the serum sLOX-1 level to be the expired air CO concentration (β= 0.182, p<0.05) and the hsCRP level (β= 0.213, p<0.01). The serum sLOX-1 level was found to increase in close association with both the smoking-related variables and the inflammatory marker hsCRP. These findings suggest that LOX-1 may therefore play an important role in the onset of smoking-induced inflammation and atherosclerosis in humans.

Increased Circulating Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor (sLOX-1) and Increased Endothelial Cell Expression of LOX-1 in Sickle Cell Disease (SCD): A Novel Marker for SCD Vasculopathy?

Abstract 246 Introduction:Inflammation and abnormal adhesion of sickle red blood cells (RBCs), leukocytes and platelets to the vascular endothelium are postulated to play a central role in the pathogenesis of vaculopathy associated with sickle cell disease (SCD). Dysfunctional endothelial cells in the SCD vaso-occlusive process display vasoconstriction, proinflammatory and prothrombotic changes. Sickle RBCs may damage or activate the endothelium via enhanced expression of cell surface adhesion molecules such as vascular cell adhesion molecule (VCAM), intercellular adhesion molecules (ICAM), platelet endothelial cellular adhesion marker (PECAM), E- selectin, and P-selectin. In addition, SCD modulates high levels of circulating soluble adhesion molecules especially during the sickle cell crisis. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is an endothelial cell receptor for oxidized low-density lipoprotein. The enhanced expression of LOX-1 in endothelial cells has been identified in a variety of pathologic conditions including atherosclerosis, diabetic vasculopathy, hyperlipidemia and inflammation. The purpose of this study is to investigate changes in the expression of LOX-1 and its potential role in the pathogenesis of SCD vasculopathy. Methods:Using real time quantitative PCR, we analyzed LOX-1 gene expression in cultured human coronary endothelial cells (HCEC) following static incubation with sickle RBCs. We also measured circulating soluble LOX-1 (sLOX-1) concentrations by sandwich ELISA assay in SCD patient plasma. The statistical analysis was performed using Student's t-test. Results:LOX-1 gene expression in HCEC was significantly increased by incubation with sickle RBCs compared with normal RBCs. Upregulation was detected after 1 hour of incubation, and reached a peak after 6 hours. We studied 48 SCD (hemoglobin SS) patients (26 female, 22 male); vs 17 healthy (hemoglobin 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 SCD patients (mean: 3.05±2.53 ng/mL; range 0.30 – 11.30 ng/mL) was significantly higher (p=0.0046) than in control healthy subjects (mean: 1.27±0.81 ng/mL). In the 15 SCD patients with VOC, sLOX-1 concentrations were higher, (mean: 3.65±2.40 ng/mL). Conclusions:Our study reveals that LOX-1 gene expression in endothelial cells is upregulated by incubation with SCD erythrocytes. Baseline circulating sLOX-1 levels are elevated in SCD patients compared with healthy controls. sLOX-1 levels are further elevated in VOC. Enhanced LOX-1 expression in endothelial cells may play a role in the pathophysiology of SCD vasculopathy. 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. Disclosures:Green:Emisphere - Consultancy: Consultancy; Teva Pharmaceuticals - expert testimony: Consultancy.

Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels predict percutaneous coronary intervention-related periprocedural myocardial infarction in stable patients undergoing elective native single-vessel PCI

Percutaneous coronary intervention-related periprocedural myocardial infarction (PCI-RPMI) has now been definitively linked in large data sets to long-term adverse outcomes. It is more likely that the relationship is caused by the underlying predisposing factors that led to the PCI-RPMI, such as plaque vulnerability. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in multiple phases of vascular dysfunction, including atherosclerotic plaque formation and/or vulnerability. The purpose of this study was to determine whether soluble LOX-1 (sLOX-1) is associated with myocardial necrosis in elective native single-vessel PCI (NSV-PCI). From January 2010 to January 2012, 214 consecutive stable patients undergoing elective NSV-PCI were enrolled. Troponin T, CK and CK-MB were performed to screen for PCI-induced myocardial necrosis after the procedure, and PCI-RPMI was defined as three times the ULN of CK, which was confirmed by the elevation of the CK-MB and troponin T. According to the cardiac biomarkers result, patients were divided into two groups [PCI-RPMI(+) and PCI-RPMI(-)]. sLOX-1 levels were measured in serum by ELISA. Of the 214 patients who underwent NSV-PCI, 33 (15.4%) patients developed PCI-RPMI. The results of this study showed that among patients undergoing elective NSV-PCI, those with PCI-RPMI had significantly higher circulating sLOX-1 levels than those without (167±89 vs. 99±68pg/mL; p<0 0.001). There were high correlations between sLOX-1 levels and CK and CK-MB values (r=0.677 and r=0.682, respectively; p<0.001). Our study demonstrated that circulating sLOX-1 levels were associated with PCI-RPMI, which might predict periprocedural myocardial necrosis in elective NSV-PCI. Importantly, the study speculates that the level of sLOX-1 may help to identify patients at risk for PCI-RPMI before the procedure. sLOX-1 may provide new insights into not only risk stratification, but also therapeutic strategies for elective PCI.

Pregnancy Followed by Delivery May Affect Circulating Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels in Women of Reproductive Age

Background/Objective. It is known that menopause or lack of endogenous estrogen is a risk factor for endothelial dysfunction and CAD. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved inmultiple phases of vascular dysfunction.The purpose of the current study was to determine the association between soluble LOX-1 (sLOX-1) and pregnancy followed by delivery in women of reproductive age. Materials/Methods. Sixty-eight subjects with pregnancy followed by delivery (group 1) and 57 subjects with nongravidity (group 2) were included in this study. Levels of sLOX-1 were measured in serum by EL SA. Results. Plasma levels of sLOX-1 were significantly lower in Group 1 than Group 2 in women of reproductive age (0.52 ± 0.18 ng/mL and 0.78 ± 0.13, resp., P < 0.001). There were strong correlations between sLOX-1 levels and the number of gravida (r = −0.645, P < 0.001). The levels of sLOX-1 highly correlated with the number of parous (r = −0.683, P < 0.001). Conclusion. Our study demonstrated that serum sLOX-1 levels were associated with pregnancy followed by delivery that might predict endothelial dysfunction. We conclude that pregnancy followed by delivery may delay the beginning and progress of arteriosclerosis and its clinical manifestations in women of reproductive age.

Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are associated with proximal/middle segment of the LAD lesions in patients with stable coronary artery disease

Atherosclerosis is the main underlying pathology of coronary artery disease (CAD), which is the leading cause of mortality worldwide. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved in multiple phases of vascular dysfunction, including endothelial dysfunction, atherosclerotic plaque formation, and destabilization. The purpose of the current study was to determine whether soluble LOX-1 is associated with proximal/mid and distal segment of the left anterior descending (LAD) artery lesion in patients with stable CAD. Sixty-four patients with proximal/mid segment of the LAD lesions and 51 patients with distal segments of the LAD lesions were included in this study. Soluble LOX-1 levels were measured in all study subjects. Baseline characteristics of the two groups were similar. In stable CAD, patients with proximal/middle segment of the LAD lesions had significantly higher circulating soluble LOX-1 levels than patients with distal segments of the LAD lesions (1.07±0.33 vs. 0.70±0.17ng/ml, p<0.001). No correlation was found between plasma-soluble LOX-1 levels and fasting glucose, lipid profile. For predicting proximal/middle LAD lesions, the highest specificity (95,2%) and sensitivity (53,8%) levels were obtained at the cut-off value of 0.68. Our study demonstrated that serum-soluble LOX-1 levels were associated with proximal/mid segment of the LAD lesions. Furthermore, this study suggested soluble LOX-1 might be a useful biomarker of coronary plaque vulnerability in patients with stable CAD. Soluble LOX-1, the novel biochemical marker, may provide new insights into not only risk stratification but also therapeutic strategy for CAD.

CRP enhances soluble LOX-1 release from macrophages by activating TNF-α converting enzyme

Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. We hypothesized that the inflammatory marker C-reactive protein (CRP) might stimulate sLOX-1 release by activating tumor necrosis factor-α converting enzyme (TACE). Macrophages differentiated from THP-1 cells were stimulated with TNF-α and further treated with CRP in the absence or presence of specific inhibitors or small interfering RNA (siRNA). Our results showed that CRP increased sLOX-1 release from activated macrophages in a dose-dependent manner and that these effects were regulated by Fc γ receptor II (FcγRII)-mediated p47(phox) phosphorylation, reactive oxygen species (ROS) production, and TACE activation. CRP also enhanced sLOX-1 release from macrophages derived from peripheral blood mononuclear cells (PBMC) of patients with acute coronary syndrome (ACS). Pretreatment with antibody against FcγRII or with CD32 siRNA, p47(phox) siRNA, apocynin, N-acetylcysteine, tumor necrosis factor-α protease inhibitor 1 (TAPI-1) or TACE siRNA attenuated sLOX-1 release induced by CRP. CRP also elevated serum sLOX-1 levels in a rabbit model of atherosclerosis. Thus, CRP might stimulate sLOX-1 release, and the underlying mechanisms possibly involved FcγRII-mediated p47(phox) phosphorylation, ROS production, and TACE activation.

Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a sensitive and specific biomarker for acute coronary syndrome—Comparison with other biomarkers

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) appears to be involved in atherosclerotic plaque vulnerability and rupture. Circulating soluble LOX-1 (sLOX-1) levels are dramatically elevated in patients with acute coronary syndrome (ACS), and its diagnostic sensitivity and specificity is superior to high-sensitivity C-reactive protein (hs-CRP). In this study, we have compared the diagnostic value of sLOX-1 for ACS with those of troponin T (TnT) and heart-type fatty acid binding protein (H-FABP). One hundred and seven patients who underwent coronary angiography (CAG), including 18 ACS and 89 non-ACS patients were enrolled. Peripheral blood samples were obtained during the emergent or elective CAG. The non-ACS group consisted of 30 patients with normal CAG, 30 stable angina pectoris patients controlled by medical treatment, and 29 patients with stable angina who required elective coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft). Age, gender, lipid profiles, or prevalence of diabetes, smoking, or hypertension were not significantly different between ACS and non-ACS. These factors did not significantly affect blood sLOX-1 levels. Circulating sLOX-1, TnT, and H-FABP levels were significantly higher in ACS than non-ACS. Area under the curve (AUC) values of the receiver-operating characteristic curves were 0.948, 0.704, and 0.691 for sLOX-1, TnT, and H-FABP, respectively. In a TnT-negative (<0.03 ng/mL) subgroup, the AUC values for sLOX-1 and H-FABP were 0.848 and 0.476, respectively. Circulating sLOX-1 is a more sensitive and specific biomarker for ACS than TnT and H-FABP, and provides additional diagnostic values when measured in combination with TnT.