High Plasma Levels of Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor-1 Are Associated With Inflammation and Cardiometabolic Risk Profiles in Pediatric Overweight and Obesity.

Background Lectin-like oxidized low-density lipoprotein (ox-LDL) receptor-1 is a scavenger receptor for oxidized low-density lipoprotein. In adults, higher soluble lectin-like ox-LDL receptor-1 (sLOX-1) levels are associated with cardiovascular disease, type 2 diabetes, and obesity, but a similar link in pediatric overweight/obesity remains uncertain. Methods and Results Analyses were based on the cross-sectional HOLBAEK Study, including 4- to 19-year-olds from an obesity clinic group with body mass index >90th percentile (n=1815) and from a population-based group (n=2039). Fasting plasma levels of sLOX-1 and inflammatory markers were quantified, cardiometabolic risk profiles were assessed, and linear and logistic regression analyses were performed. Pubertal/postpubertal children and adolescents from the obesity clinic group exhibited higher sLOX-1 levels compared with the population (P<0.001). sLOX-1 positively associated with proinflammatory cytokines, matrix metalloproteinases, body mass index SD score, waist SD score, body fat %, plasma alanine aminotransferase, serum high-sensitivity C-reactive protein, plasma low-density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure SD score, and inversely associated with plasma high-density lipoprotein cholesterol (all P<0.05). sLOX-1 positively associated with high alanine aminotransferase (odds ratio [OR], 1.16, P=4.1 E-04), insulin resistance (OR, 1.16, P=8.6 E-04), dyslipidemia (OR, 1.25, P=1.8 E-07), and hypertension (OR, 1.12, P=0.02). Conclusions sLOX-1 levels were elevated during and after puberty in children and adolescents with overweight/obesity compared with population-based peers and associated with inflammatory markers and worsened cardiometabolic risk profiles. sLOX-1 may serve as an early marker of cardiometabolic risk and inflammation in pediatric overweight/obesity. Registration The HOLBAEK Study, formerly known as The Danish Childhood Obesity Biobank, ClinicalTrials.gov identifier number NCT00928473, https://clinicaltrials.gov/ct2/show/NCT00928473 (registered June 2009).

sLOX-1: A Molecule for Evaluating the Prognosis of Recurrent Ischemic Stroke.

Several clinical parameters and biomarkers have been proposed as prognostic markers for stroke. However, it has not been clarified whether the risk factors affecting the prognosis of patients with recurrent and first-ever stroke are similar. In this study, we aimed to explore the relationship between soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) levels and the prediction of the functional outcome in patients with recurrent and first-ever stroke. A total of 266 patients with recurrent and first-ever stroke, who underwent follow-up for 3 months, were included in this study. Plasma samples were collected within 24 h after onset. The results showed that biomarkers for the prognosis of patients with recurrent stroke were different from that of those with first-ever stroke. sLOX-1 levels were correlated with modified Rankin Scale scores of patients with recurrent stroke alone (r = 0.3232, p = 0.001). sLOX-1 levels were also associated with an increased risk of unfavorable outcomes in patients with recurrent stroke with an adjusted odds ratio of 1.489 (95% confidence interval, 1.204-1.842, p < 0.0001). Combining the risk factors showed greater accuracy for prognosis, yielding a sensitivity of 93.2% and a specificity of 75%, with an area under the curve of 0.916, evaluated by the receiver operating characteristic curve. These findings suggest that the diagnosis and prognosis are different between patients with recurrent stroke and those with first-ever stroke, and sLOX-1 level is an independent prognostic marker in patients with recurrent stroke.

Role of Plasma Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 and microRNA-98 in Severity and Risk of Coronary Artery Disease.

BACKGROUND: Coronary artery diseases are the most important cause of premature death, and these diseases are predominantly related to atherosclerosis. Soluble lectin-like oxidized low-density lipoprotein receptor-1 and microRNAs are closely associated with atherosclerotic coronary heart diseases. AIMS: To investigate the relationship between the severity and risk of coronary artery disease and plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 and miR-98. STUDY DESIGN: Case-control study. METHODS: Angiographically documented patients with 38 single-vessel, 75 double-vessel, and 62 multi-vessel coronary artery disease; 62 healthy control participants; and 24-hour hypoxic (1% oxygen) human umbilical vein endothelial cells were included in this study. Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 concentrations were determined through enzyme-linked immunosorbent assays, and miR-98 expressions were measured by quantitative real-time polymerase chain reaction. RESULTS: The expressions of plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels were progressively and significantly higher in patients with single-vessel, double-vessel, and multi-vessel coronary artery disease than in healthy controls (p<0.001). Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 concentrations in female patients with multi-vessel, double-vessel, and single-vessel coronary artery disease had evidently elevated compared with that in male patients (p<0.001). Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels were remarkably increased in females with coronary artery disease in different age groups compared with the males in the same age groups (p<0.001). Patients with single-vessel (areas under the curve=0.879), double-vessel (area under the curve=0.928), and multi-vessel (area under the curve=0.943) coronary artery disease have been clearly differentiated from healthy participants with respect to high sensitivity and specificity. The expression of miR-98 was noticeably downregulated in patients with single-, double- and multi-vessel occluded coronary artery disease and in hypoxic human umbilical vein endothelial cell compared with controls (p<0.001). Significantly elevated lectin-like oxidized low-density lipoprotein receptor-1 and caspase-3 activity and remarkably decreased cellular viability in hypoxic injured human umbilical vein endothelial cell. On the contrary, mimic of miR-98 markedly reduced caspase-3 and lectin-like oxidized low-density lipoprotein receptor-1 levels and highly increased cellular viability. CONCLUSION: Elevated circulating plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels have a potential impact to identify the severity of coronary artery disease and have a strong correlation with aging as well as the female gender. Reduced plasma miR-98 level is possibly considered a risk factor for coronary artery disease, and agomiR-98 prevents atherosclerosis and cellular injury by targeting lectin-like oxidized low-density lipoprotein receptor-1.

Lipidomics links oxidized phosphatidylcholines and coronary arteritis in Kawasaki disease.

AIMS: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. CONCLUSION: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD.

Role of LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1) as a Cardiovascular Risk Predictor: Mechanistic Insight and Potential Clinical Use.

Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a worldwide cause of morbidity and mortality. Reducing ApoB-containing lipoproteins-chiefly, LDL (low-density lipoprotein)-has been the main strategy for reducing CVD risk. Although supported by large randomized clinical trials, the persistence of residual cardiovascular risk after effective LDL reduction has sparked an intense search for other novel CVD biomarkers and therapeutic targets. Recently, Lox-1 (lectin-type oxidized LDL receptor 1), an innate immune scavenger receptor, has emerged as a promising target for early diagnosis and cardiovascular risk prediction and is also being considered as a treatment target. Lox-1 was first described as a 50 kDa transmembrane protein in endothelial cells responsible for oxLDL (oxidized LDL) recognition, triggering downstream pathways that intensify atherosclerosis via endothelial dysfunction, oxLDL uptake, and apoptosis. Lox-1 is also expressed in platelets, where it enhances platelet activation, adhesion to endothelial cells, and ADP-mediated aggregation, thereby favoring thrombus formation. Lox-1 was also identified in cardiomyocytes, where it was implicated in the development of cardiac fibrosis and myocyte apoptosis, the main determinants of cardiac recovery following an ischemic insult. Together, these findings have revealed that Lox-1 is implicated in all the main steps of atherosclerosis and has encouraged the development of immunoassays for measurement of sLox-1 (serum levels of soluble Lox-1) to be used as a potential CVD biomarker. Finally, the recent development of synthetic Lox-1 inhibitors and neutralizing antibodies with promising results in animal models has made Lox-1 a target for drug development. In this review, we discuss the main findings regarding the role of Lox-1 in the development, diagnosis, and therapeutic strategies for CVD prevention and treatment.

Identification of plaque ruptures using a novel discriminative model comprising biomarkers in patients with acute coronary syndrome.

Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), neutrophil gelatinase-associated lipocalin (NGAL), and matrix metalloproteinase-9 (MMP-9) are inflammatory biomarkers involved in plaque destabilization resulting in acute coronary syndrome (ACS). This study aimed to investigate the diagnostic value of a combination of biomarkers to discriminate plaque ruptures in the setting of ACS. Eighty-five ACS patients with optical coherence tomography (OCT) images of the culprit plaque were included and categorized into two groups: ACS with plaque rupture (Rupture group, n = 42) or without plaque rupture (Non-rupture group, n = 43) verified by OCT. A discriminative model of plaque rupture using several biomarkers was developed and validated. The Rupture group had higher white blood cell (WBC) counts and peak creatine kinase-myocardial band (CK-MB) levels (13.39 vs. 2.69 ng/mL, p = 0.0016). sLOX-1 (227.9 vs. 51.7 pg/mL, p < 0.0001) and MMP-9 (13.4 vs. 6.45 ng/mL, p = 0.0313) levels were significantly higher in the Rupture group, whereas NGAL showed a trend without statistical significance (59.03 vs. 53.80 ng/mL, p = 0.093). Receiver operating characteristic curves to differentiate Rupture group from Non-rupture group calculated the area under the curve for sLOX-1 (p < 0.001), MMP-9 (p = 0.0274), and NGAL (p = 0.0874) as 0.763, 0.645, and 0.609, respectively. A new combinatorial discriminative model including sLOX-1, MMP-9, WBC count, and the peak CK-MB level showed an area under the curve of 0.8431 (p < 0.001). With a cut-off point of 0.614, the sensitivity and specificity of plaque rupture were 62.2% and 97.6%, respectively. The new discriminative model using sLOX-1, MMP-9, WBC count, and peak CK-MB levels could better identify plaque rupture than each individual biomarker in ACS patients.

Early identification of carotid vulnerable plaque in asymptomatic patients.

BACKGROUND: This study was to explore the influencing factors of atherosclerotic plaque formation and stability in patients with asymptomatic carotid atherosclerotic plaques, so as to identify the vulnerable plaques at early stage, and then find high-risk group of cardio-cerebrovascular events for early clinical intervention to reduce related mortality and disability. METHODS: A total of 302 enrolled patients with asymptomatic carotid atherosclerotic plaques were divided into 3 groups based on the results of carotid artery color Doppler ultrasound: atherosclerotic unstable plaque (UP) group, atherosclerotic stable plaque (SP) group, and control group without plaques. Serum markers were measured by ELISA. χ2 test, t test, Pearson correlation analysis, and Logistic multivariate regression analysis were used in the analysis, and P < 0.05 was considered statistically significant. RESULTS: It revealed that high MMP-9, LOX-1and YKL-40 were independent risk factors for unstable plaque formation. The area under the curve (AUC) of serum markers combined with MMP-9, LOX-1 and YKL-40 was 0.850, with sensitivity 87.67%, specificity 81.13%, and diagnostic accuracy 84.92%, which was significantly better than the individual diagnostic efficacy of other three factors. The accuracy rate of Crouse Plaque Score (CPS) in the diagnosis of vulnerable plaques was 61.90%, the 10-year ICVD diagnosis accuracy rate was 56.75%, and the diagnostic accuracy of serum markers was significantly better than CPS and 10-year ICVD. CONCLUSION: Noninvasive cervical color Doppler ultrasound combined with serum markers MMP-9, LOX-1 and YKL-40 have significant early recognition effect on asymptomatic carotid vulnerable plaque patients.

Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Is Inversely Correlated with the Activity of ANCA-Associated Vasculitis.

Lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) binds to oxidized LDL, which is associated with inflammation in various vascular disorders. Here, we aimed to investigate the potential of soluble LOX1 (sLOX1) as an indicator of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) activity. Serum levels of sLOX1 in frozen samples from patients with AAV enrolled in a prospective observational cohort study at the Severance Hospital were measured using enzyme-linked immunosorbent assay. Clinical and laboratory data were collected on the date when the blood sampling was performed. The association between sLOX1 and clinical and laboratory data was assessed using Pearson's correlation analysis. The median age of the recruited 79 patients was 62.0 years, and 27 (34.2%) patients were men. The median Birmingham vasculitis activity score (BVAS), five-factor score, vasculitis damage index, and sLOX1 level were 6, 1, 3, and 911.9 pg/mL, respectively. Correlation analysis based on BVAS revealed that sLOX1 and total cholesterol were significantly inversely correlated with BVAS (r=-0.224, p=0.047 and r=-0.424, p<0.001, respectively). No significant correlations were observed between continuous variables and sLOX1 except for BVAS, although total cholesterol tended to correlate with sLOX1 (r=0.190, p=0.093). Additionally, sLOX1 was not influenced by sex, hypertension, diabetes mellitus, or the presence of pulmonary, cardiovascular, and renal involvement of AAV. In summary, sLOX1 was inversely correlated with BVAS in AAV patients, which is different from other vascular diseases or inflammatory diseases.

Magnesium Sulfate Administration in Moderate Coronary Artery Disease Patients Improves Atherosclerotic Risk Factors: A Double-Blind Clinical Trial Study.

Magnesium (Mg) deficiency is known to promote vascular and cardiac dysfunctions such as atherosclerosis. This study investigated the effect of oral MgSO4 therapy to improve lipid profile and serum oxidized LDL level and its receptor (LOX1) in moderate coronary atherosclerotic patients. In this randomized double-blind placebo-controlled clinical trial study, 64 patients with moderate coronary artery disease were selected according to angiography findings. Participants were divided into 2 groups including Mg-treated (n = 32) and placebo (n = 32) The patients received either placebo or MgSO4 supplement capsule, containing 300 mg MgSO4 for 6 months on a daily basis. Lipid profile, HbA1c, 2h postprandial (2hpp) blood glucose, fasting blood sugar, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), oxidized low-density lipoprotein, and lectin-like ox-LDL receptor 1 (LOX1) concentrations were measured at baseline and every 3 months. HbA1c, serum LOX1, and oxidized low-density lipoprotein concentrations were significantly lower in the Mg-treated group than the placebo group 3 months after MgSO4 administration. 2hpp, serum low-density lipoprotein cholesterol, SGPT, SGOT levels, and HbA1c levels significantly improved in the Mg-treated group compared with the placebo-received group. Overall, the results of this study showed that magnesium treatment improved some of the major risk factors of atherosclerosis. According to the results of liver function tests (SGOT and SGPT), magnesium therapy seems to be safe in patients with moderate atherosclerotic plaque. Therefore, it is suggested that magnesium to be used along with other atherosclerosis control drugs.

Polycystic ovary syndrome and endothelial dysfunction: A potential role for soluble lectin-like oxidized low density lipoprotein receptor-1.

The aims of this study were to investigate whether serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), oxidized LDL (oxLDL), paraoxonase-1(PON-1) and hydroperoxide (LOOH) levels are altered in women with polycystic ovary syndrome (PCOS) and also to determine if hyperandrogenism, insulin resistance (IR) and Anti-Müllerian Hormone (AMH) are associated with endothelial dysfunction in PCOS. A total of 46 women with PCOS and 46 non-PCOS healthy controls were recruited. Women with PCOS had significantly higher sLOX-1, oxLDL and LOOH concentrations than non-PCOS women [6.16 (3.92-13.95) vs 1.37 (0.63-4.43) ng/mL, p < 0.001; 6.48 ± 1.03 vs 3.16 ± 1.02 µU/L, p < 0.001; 2.45 (1.45-3.45) vs 1.06 (0.64-1.56) µmol/L, p < 0.001]. The mean PON-1 level of PCOS group was lower than non-PCOS group (69.47 ± 10.75 vs 104.08 ± 21.43 U/mL, p < 0.001). There was no significant difference in terms of the sLOX-1, oxLDL, LOOH and PON-1 levels between normal weight and overweight PCOS women. On univariate logistic regression analysis, Ferriman-Gallwey scale (FGS), HOMA-IR and AMH were an independent predictors of high risk group of endothelial dysfunction markers (HR-EDm). Age and BMI were not associated with HR-EDm. When incorporated into the multivariate model, endotelial dysfunction markers independently correlated with clinical hyperandrogenism (FGS) but not with AMH. In conclusion, our results indicated that an increased concentration of sLOX-1 might be an early predictor of endothelial damage in patients with PCOS. Women with PCOS have elevated sLOX-1, oxLDL, LOOH and decreased PON-1 levels, independent of BMI. Endothelial dysfunction in women with PCOS is associated with hyperandrogenism. Further studies are required to confirm our findings.

Serum LOX-1 is a novel prognostic biomarker of colorectal cancer.

BACKGROUND: Colorectal cancer is the third most common cancer worldwide. If biomarkers can be identified in liquid biopsy, diagnosis and treatment can be optimized even when cancerous tissues are not available. The purpose of this study was to identify proteins from liquid biopsy that would be useful as markers of poor prognosis. METHODS: First, we comprehensively analyzed serum proteins to identify potential biomarkers and focused on serum lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). The relationship between LOX-1 and the prognosis of patients with colorectal cancer has not been reported. Next, we validated this marker using serum samples from 238 patients with colorectal cancer by ELISA and 100 tissue samples by immunohistochemical staining. RESULTS: The optimal cut-off value of serum LOX-1 was 538.7 pg/mL according to time-dependent receiver operating characteristics curve analysis. The overall survival of patients with high levels of serum LOX-1 was significantly poorer than that of individuals with low levels of LOX-1 in the training and test datasets. In multivariate analysis for overall survival, serum LOX-1 was an independent prognostic factor identified in liquid biopsy (hazard ratio = 1.729, p = 0.027). The prognosis of patients with high LOX-1 expression in tumor tissues was significantly poorer than that of individuals with low expression (p =0.047 ). Additionally, inflammatory factors such as white blood cell count, C-reactive protein level, neutrophil/lymphocyte ratio, and monocyte/lymphocyte ratio were significantly higher in the group with high serum LOX-1 levels. CONCLUSIONS: Serum LOX-1 might be a useful biomarker of poor prognosis in colorectal cancer.

LOX-1: A potential driver of cardiovascular risk in SLE patients.

Traditional cardiovascular disease (CVD) risk factors, such as hypertension, dyslipidemia and diabetes do not explain the increased CVD burden in systemic lupus erythematosus (SLE). The oxidized-LDL receptor, LOX-1, is an inflammation-induced receptor implicated in atherosclerotic plaque formation in acute coronary syndrome, and here we evaluated its role in SLE-associated CVD. SLE patients have increased sLOX-1 levels which were associated with elevated proinflammatory HDL, oxLDL and hsCRP. Interestingly, increased sLOX-1 levels were associated with patients with early disease onset, low disease activity, increased IL-8, and normal complement and hematological measures. LOX-1 was increased on patient-derived monocytes and low-density granulocytes, and activation with oxLDL and immune-complexes increased membrane LOX-1, TACE activity, sLOX-1 release, proinflammatory cytokine production by monocytes, and triggered the formation of neutrophil extracellular traps which can promote vascular injury. In conclusion, perturbations in the lipid content in SLE patients' blood activate LOX-1 and promote inflammatory responses. Increased sLOX-1 levels may be an indicator of high CVD risk, and blockade of LOX-1 may provide a therapeutic opportunity for ameliorating atherosclerosis in SLE patients.

Serum soluble lectin-like oxidized low-density lipoprotein receptor-1 as a biomarker of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI) greatly contributes to the high morbidity and mortality of aneurysmal subarachnoid hemorrhage (aSAH) patients. Expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was substantially raised in the basilar arterial wall of SAH rabbits. We attempted to ascertain the relationship between serum soluble LOX-1 (sLOX-1) levels and the occurrence of DCI after aSAH. MATERIALS AND METHODS: We enrolled 125 aSAH patients and 125 healthy controls. Serum sLOX-1 levels were quantified using commercial enzyme-linked immunosorbent assay kit. The relationship between sLOX-1 levels and DCI was analyzed utilizing the multivariate logistic regression analysis. RESULTS: Serum sLOX-1 levels were significantly higher in stroke patients than in controls (median: 1,450.2 vs. 445.7 pg/ml, p < .001). Serum sLOX-1 levels were highly correlated with World Federation of Neurological Surgeons (WFNS) scores, Hunt-Hess scores, and modified Fisher scores (r = .574, .625, and .569, respectively). Forty-two patients (33.6%) experienced DCI. Serum sLOX-1 > 1,450.2 pg/ml, WFNS scores and modified Fisher scores were the independent predictors of DCI. Under receiver operating characteristic curve, serum sLOX-1 levels exhibited a significant discriminatory capability (area under curve 0.825, 95% confidence interval 0.747-0.887). The predictive power of serum sLOX-1 levels was similar to those of WFNS scores and modified Fisher grade (both p > .05). Moreover, serum sLOX-1 levels significantly improved their predictive capability (both p < .05). CONCLUSIONS: Serum soluble LOX-1, in positive association with hemorrhagic severity, appears to have the potential to become a promising predictor of DCI after aSAH.

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

OBJECTIVE: Although 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). METHODS: 39 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. RESULTS: PORH-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). CONCLUSION: These data suggest that cutaneous microvascular endothelial function is impaired in patients with CSF, which is closely associated with increased LOX-1 expression.

Detection of a High Ratio of Soluble to Membrane-Bound LOX-1 in Aspirated Coronary Thrombi From Patients With ST-Segment-Elevation Myocardial Infarction.

Background The circulating level of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) is a valuable biomarker of acute myocardial infarction (AMI). The most electronegative low-density lipoprotein, L5, signals through LOX-1 to trigger atherogenesis. We examined the characteristics of LOX-1 and the role of L5 in aspirated coronary thrombi of AMI patients. Methods and Results Intracoronary thrombi were aspirated by performing interventional thrombosuction in patients with ST-segment-elevation myocardial infarction (STEMI; n=32) or non-ST-segment-elevation myocardial infarction (n=12). LOX-1 level and the ratio of sLOX-1 to membrane-bound LOX-1 were higher in thrombi of STEMI patients than in those of non-ST-segment-elevation myocardial infarction patients. In all aspirated thrombi, LOX-1 colocalized with apoB100. When we explored the role of L5 in AMI, deconvolution microscopy showed that particles of L5 but not L1 (the least electronegative low-density lipoprotein) quickly formed aggregates prone to retention in thrombi. Treating human monocytic THP-1 cells with L5 or L1 showed that L5 induced cellular adhesion and promoted the differentiation of monocytes into macrophages in a dose-dependent manner. In a second cohort of AMI patients, the L5 percentage and plasma concentration of sLOX-1 were higher in STEMI patients (n=33) than in non-ST-segment-elevation myocardial infarction patients (n=25), and sLOX-1 level positively correlated with L5 level in AMI patients. Conclusions The level of LOX-1 and the ratio of sLOX-1 to membrane-bound LOX-1 in aspirated thrombi, as well as the circulating level of sLOX-1 were higher in STEMI patients than in non-ST-segment-elevation myocardial infarction patients. L5 may play a role in releasing a high level of sLOX-1 into the circulation of STEMI patients.

Oxidised Low-Density Lipoprotein and Its Receptor-Mediated Endothelial Dysfunction Are Associated with Coronary Artery Lesions in Kawasaki Disease.

The study aimed to investigate the role of oxidised low-density lipoprotein (oxLDL)/lectin-like-oxLDL receptor-1 (LOX-1) in coronary artery lesions (CALs) in Kawasaki disease (KD) and of plasma oxLDL concentration in the early prediction of CALs in KD. This prospective study included 80 KD patients, 20 febrile and 20 healthy children. oxLDL, LOX-1 and other parameters were analysed in the acute phase. Plasma oxLDL concentration and LOX-1 mRNA expression in peripheral blood mononuclear cells (PBMCs) were significantly increased in KD patients compared with febrile and healthy children (P < 0.001 and P = 0.022, respectively), particularly in the group with CALs (P < 0.001 and P = 0.027, respectively). Coronary Z-score was significantly correlated with plasma oxLDL concentration and LOX-1 mRNA expression (r = 0.739 and 0.637, respectively; P < 0.01). The sensitivity and specificity of predicting CALs were 71.4% and 77.2%, respectively, at plasma oxLDL concentration ≥ 12.38 mU/L. oxLDL/LOX-1 may be involved in CAL development. The plasma oxLDL concentration in the acute phase is a potentially useful biological indicator for predicting CAL in KD patients.

Evaluation of hs-CRP and sLOX-1 Levels in Moderate-to-High Risk Acute Coronary Syndromes.

OBJECTIVE: Risk stratification and prompt treatment are essential for the management of acute coronary syndromes (ACS) and prediction of future prognosis. Subclinical vascular inflammation and novel biomarkers play an important role in the clinical evaluation of ACS patients. METHODS: We enrolled patients who were admitted to emergency service with unstable angina or non- ST segment elevated ACS (NSTE-ACS) in the study population. Coronary artery disease (CAD) complexity was determined via evaluation of angiographical views and peripheral venous blood samples were collected to measure highly sensitive C-reactive protein (hs-CRP) and soluble form of Lectin-like OxLDL receptor-1 (sLOX-1) levels. RESULTS: A total of 40 patients were enrolled in the study population, mean age was 65.1±13.8 years and male gender percentage was 52.5%. Twenty-nine of patients had NSTE-ACS and 11 patients had unstable angina presentation. The modified Gensini scores were higher for patients with elevated hs- CRP and sLOX-1 levels. CONCLUSION: Vascular inflammation displays the onset of ACS and it is related to more complex CAD in these patients. An increase in sLOX-1 expression is closely related to anatomical complexity of CAD in ACS.

Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 Predicts the Changes of Rheumatoid Factor Titers in Rheumatoid Arthritis.

OBJECTIVE: The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis. METHODS: We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression. RESULTS: Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF. CONCLUSIONS: The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.

Stratification by Multidimensional Approach for Rational Treatment of Asymptomatic Carotid Stenosis (SMART-K Study): Study Protocol.

With recent advances in medical treatments for carotid artery stenosis (CS), indications for carotid surgery should be more carefully considered for asymptomatic CS (ACS). Accurate stratification of ACS should be based on the risk of cerebral infarction, and subgroups of patients more likely to benefit from surgical treatment should be differentiated. Magnetic resonance imaging (MRI) offers a non-invasive, accurate modality for characterizing carotid plaque. Intraplaque hemorrhage (IPH) seems the most promising feature of vulnerable plaque detectable by MRI. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a type II membrane protein of the C-type lectin family with an extracellular domain that can be proteolytically cleaved and released as a soluble form (sLOX-1). This sLOX-1 plays a key role in the pathogenesis of atherosclerosis, and elevated sLOX-1 concentrations correlate with thin or ruptured fibrous caps in patients with acute coronary syndrome. This ongoing study aims to clarify the incidence of ischemic stroke in patients with ACS and IPH confirmed by MRI, and to assess whether sLOX-1 could provide a biomarker for risk of future ischemic events. The study population comprises patients with ACS (>60% area stenosis) associated with MRI-diagnosed IPH receiving follow-up under medical treatment. Primary endpoints comprise transient ischemic attack, stroke or amaurosis resulting from concerned CS. Secondary endpoints comprise any stroke or surgical treatment for progressive luminal stenosis. The target number of patients is 120 and the observational period is 36 months. The study results could help identify individuals with ACS who are refractory to medical therapy.